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No More Heroes 2: Desperate Struggle (ノーモア★ヒーローズ デスパレート ストラグル Nō Moa Hīrōzu Desuparēto Sutoraguru) is a hack and slash video game for the released for the Wii. It is the sequel to the original game, directed by Nobutaka Ichiki (with Suda51 being the executive director), developed by Grasshopper Manufacture, published by Marvelous Entertainment, Rising Star Games and XSEED Games.

A port of the game for Nintendo Switch was released on October 28, 2020, for the Amazon Luna on February 25, 2021, and for Microsoft Windows on June 9, 2021.

Plans for a No More Heroes sequel were first revealed shortly after the release of the first game, in a March 15, 2008 interview with Computer and Video Games, where Suda revealed he would be interested in producing a No More Heroes 2 for the Wii, on the condition that the game sold well enough to convince its publishers. With No More Heroes' positive reception in North America, and Martin Defries, manager of Rising Star Games who were responsible for publishing No More Heroes in Europe, raving about the sales of the first game, not only was it unlikely that Suda's intention to direct a follow-up would go unsupported, but this meant it was likely that the sequel would not be published exclusively in Japan. Release dates for Desperate Struggle in North America and Europe have been confirmed. XSEED Games will be publishing the game in North America, taking over from Ubisoft, who published No More Heroes in the country.

Desperate Struggle was announced on October 8, 2008, where a teaser trailer for the game was shown at the Tokyo Game Show in Chiba, Japan. This trailer provides little insight to the premise of the game, other than that the player will once again take control of Travis Touchdown, the protagonist from the first game. Following No More Heroes' suit of pitting Travis against unique adversaries, the trailer sees Travis preparing to battle a woman fitted with a six-limbed jet pack. Also, similar to the first game's numerous references to popular culture, in the trailer Travis says the Terminator film series' catch phrase "I will be back!" before initiating a sequence with music similar to that of the Terminator series' scores. Travis' attire has apparently been modified for Desperate Struggle, as well. Instead of his signature red hot jacket and Pure White Lover Bizarre Jelly t-shirt, Travis wears a black jacket, with ragged pants and a simple t-shirt reading " TRAVIS STRIKES AGAIN " in the trailer.

Desperate Struggle is planned for release in Europe in both "extreme" and mild formats, to appeal to European fans who were disappointed by the bloodless version of No More Heroes that was published in their region. On the topic of these different formats, Suda has explained:

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Suda has also promised improvements to the game's engine as well as its graphics, resulting in "a far busier Santa Destroy" (thus confirming the town's reappearance). This may assure the senses of those who, like reviewers at GameSpot, feel the Santa Destroy of No More Heroes "should be taken as a hub rather than a city and something that should have been worked on a lot more." Another frequently criticized feature of the first game's engine is its poor collision detection. The same production staff responsible for the first game are also confirmed to have reprised their roles for the designing of Desperate Struggle.

Suda declared in an interview with Eurogamer on October 9, 2008, "When we worked on the first No More Heroes, [Grasshopper and Japanese publisher Marvelous] we were really confident that this one was going to be a huge success. When we were talking at that time we said okay, if it really becomes a success, we should definitely make a sequel. The sales in US and Europe were pretty good so we said okay, we have to make it." He has also confessed, "[No More Heroes] is the very first time that I really wanted to make a sequel, out of all the titles I've made so far."

Though Suda has remained fairly secretive of the game's premise thus far, when questioned by Eurogamer on what feeling Suda wished to convey to players through the game, he responded with, "One of the feelings you may be experiencing is the true meaning of fighting," likely a result of the game's dominant themes being revengeful in nature.

Three years have passed since Travis Touchdown became the top assassin in the United Assassins Association and walked away. Now, he returns to Santa Destroy and fights Skelter Helter, who seeks revenge on Travis for killing his older brother Helter Skelter prior to the first game. After winning the battle, he meets Sylvia Christel again, who informs him he is now ranked 51st. The dying Skelter interrupts them and warns Travis that he and his co-conspirators will still have their revenge.

The same night, a group of criminals kill Travis's best friend, Bishop, and throw his head through Travis's window in a paper bag. Travis, furious and seeking revenge, asks Sylvia to set up the next fight. Sylvia tells him that the one who ordered his death was Jasper Batt, Jr., the CEO of Pizza Bat and first-ranked assassin. In the first game, Travis stopped three different attempts by Pizza Bat (then localized as "Pizza Butt") to expand into in Santa Destroy by assassinating the CEO. In the three years since, with Travis out of the picture, Pizza Bat successfully opened a headquarters in Santa Destroy and bought out practically every business in town. Travis resolves to climb to the ranks to get a chance for revenge on Jasper.

Travis fights and defeats Nathan Copeland. He then meets Charlie MacDonald and his cheerleaders, who transform into a giant mech called the Santa Death Parade. Travis defeats them in his own mech, the Glastonbury, built by Dr. Naomi and based on a mech from his favorite anime. He feels remorse for the cheerleaders, realizing that they were harmless, but backpedals after Sylvia offers to nullify his victory. Before heading off to the next fight, he is challenged by someone ranked below him; college student Kimmy Howell. He defeats her, but spares her life, commenting that he "can't kill a co-ed". He also begins to fight the supernatural, facing Matt Helms and Cloe Walsh.

Sylvia organizes a battle royale with Travis and eleven other assassins. Dr. Letz Shake immediately kills all of the other assassins except Travis. He is glad for the opportunity to get revenge on Travis as well, having previously defeated Henry and frozen him in carbonite. Travis kills him and defrosts Henry. He also meets Shinobu, the assassin whom he spared in the first game, who now idolizes him and calls him "Master". At Sylvia's request, she fought and defeated Million Gunman and New Destroyman for Travis. Shinobu advances on Travis, but he turns her away because he feels "like the pervy teacher in a porno". Rejected, she steps out.

Travis fights a grueling battle against Ryuji. Travis crows triumphantly after Ryuji concedes, but Sylvia kills him in cold blood, criticizing Travis for showing mercy. Henry, suffering from hibernation sickness, fights Mimmy in a nightmare before awakening. He reconciles with Travis and kills the next three assassins for him: Scott Gardner, Greg Cantrell and Massimo Bellini. Travis fights Margaret Moonlight and Captain Vladimir, and convinces Sylvia not to destroy the latter's body. After defeating Alice Twilight, the penultimate assassin, he decides he's fed up with the ranked battles and the UAA. He berates Sylvia, insisting that assassins are human and that they shouldn't have to die for entertainment like it's some kind of video game. He promises to tear down the UAA after defeating Jasper.

Travis fights his way through the Pizza Bat headquarters to meet Jasper in his office. Jasper reveals that he was seeking revenge for his father and two brothers, the Pizza Bat CEOs Travis killed in a mission in the first game. Henry enters and helps Travis defeat him. At the end of the fight, Travis leaps out the window to destroy Jasper's float and kill him. Sylvia, riding Travis's motorcycle, catches him and drops him off at his motel.

Years later, Travis finds Sylvia working at a strip club and pays for private shows from her nearly every day. He never speaks or reveals his identity, instead opting to listen to her recap the events of the game. On the last day, she breaks down and cries, asking to see his face and hear his voice. Travis finally reveals himself, and says "Let's go. Santa Destroy needs us".

No More Heroes 2: Desperate Struggle received generally favourable reviews, receiving a score of 84/100 on Metacritic and GameRankings.

IGN praised the game for its quirky sense of humor, stream-lined design of the play experience, numerous pop-culture references, humorous sexual innuendo, 8-bit minigames and impressive graphics. Game Informer praised the new side-jobs and action while criticizing the repetitive voice work and occasionally rough graphics. X-Play stated that, while the navigation and minigames have improved, the story can be inconsistent in later missions and some bosses are frustrating. GameSpot called the combat system "remarkably fun and interactive" and commended the game's "excellent use of motion controls." Jonathan Holmes of Destructoid stated "It's extremely well crafted from beginning to end, and rarely (if ever) sacrifices fun for delivering a message." GameZone's Caleb Newby stated that "Desperate Struggle is so unpredictable it’s like the punch line to a parody of Japanese pop culture. Frantic and all over the map, it somehow makes it all work and gives Wii owners an amazing game for an older audience – a rare treat to find on Nintendo’s console."

Sales of No More Heroes 2 have been relatively poor. According to Electronic Entertainment Design and Research (EEDAR), the game sold less than 30,000 units in its first week of release in North America. Desperate Struggle debuted on the UK charts at number five during its release week in that region. The game was the thirteenth best-selling game in Japan during its release week at 11,373 copies sold. According to Famitsu sales data, the game sold just 16,838 copies by the end of 2010. This total was less than that of either the PlayStation 3 or Xbox 360 versions of No More Heroes: Heroes' Paradise, a remake of the original No More Heroes.

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</noinclude> In a 2009 interview with Kotaku, Suda51 stated he had no intentions of doing a sequel, but he had a change of heart due to the strong sales of the original. "I originally didn't want to make another No More Heroes," he said, "The game was supposed to be a one off dealio, but when the title did well, sequels do happen." Suda51 announced that No More Heroes 2: Desperate Struggle would be the last No More Heroes game on the Wii. He was quoted as saying "I think this is the last [No More Heroes] that is going to be developed on Wii. To expand [No More Heroes] to new possibilities, we need a new platform. Wii is a great platform, but we've done everything we can with it now." He has since clarified this statement, stating that he intends to continue No More Heroes on the Wii U, probably with a different protagonist. "I've finished the story for Travis [Touchdown]. It's completely finished in No More Heroes 2." Anything developed will involve "a different character, or something like that within the series."

In March 2011, Suda51 expressed his desire to create a third game in the series. After the reveal of the Wii U in June of that year, Suda51 stated that he has all sorts of ideas for a third No More Heroes for the new platform. In July 2011, Suda51 announced a new No More Heroes game exclusively for mobile phones on the DeNA service. He promises to make the game extremely violent and hopes the game will be released in the West. He also states that he hopes the game is successful since he has "over 100 concepts for mobile games." In January 2017, a new No More Heroes title was confirmed to be in development for Nintendo Switch. On August 30 during Nindies Spotlight presentation the title was announced as Travis Strikes Again: No More Heroes. A sequel to No More Heroes 2: Desperate Struggle, titled No More Heroes III, was announced at E3 2019 to be released in 2021 for the Nintendo Switch.