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The story begins when Ness is awakened by a meteor that has plummeted to the earth near his home, whereupon he proceeds to investigate the crash site. When Ness gets to the crash site he discovers a police road block and Porky Minch (Rendered Pokey Minch), his friend and neighbor, who tells him to go home. Later, Ness is woken up again by Porky knocking at his door, demanding help to find his brother Picky. They find him near the meteor behind a tree and wake him up. Then the three encounter an insect from the meteor named [[Buzz Buzz]] who informs Ness that he is from the future where the "universal cosmic destroyer", [[Giygas]], dominates the planet. Buzz Buzz senses great potential in Ness and instructs him to embark on a journey to seek out and record the melodies of eight "[[Your Sanctuary|sanctuaries]]," unite his own powers with the Earth's and gain the strength required to confront Giygas.
With this goal, Ness travels into mainland Onett, which is under terror by a gang known as The Sharks. The mayor of Onett frantically asks Ness to put a stop to their antics, in exchange for a key through a police-created barrier. After an encounter with The Sharks' leader, [[Frank Fly]], Ness battles the [[Titanic Ant]] and reaches the first sanctuary, [[Giant Step]]. However, because the way to the sanctuary was barricaded before Ness entered, the Onett police chief [[Captain Strong]] lectures Ness on trespassing through the barrier. Ness, however, asks Strong to allow passage to [[Twoson]], and Strong forces Ness to battle his five strongest men, plus Strong himself, to prove his strength. Ness defeats all six men, then proceeds to Twoson, where he discovers that a young girl, named [[Paula]], has been kidnapped. Paula's father suspects that [[
Everdread]], the shady owner of Twoson's Burglin Park, is responsible, and Ness confronts Everdread in the park.
After battling and defeating Everdread, he reveals that Paula has traveled to [[Happy Happy Village]], but has not returned, suspecting that the cult of Happy Happyism has captured her. Ness attempts to reach the village, but finds the bridge leading there broken. What's worse, an iron pencil statue is blocking the other route. Returning to Twoson, he encounters and befriends [[Apple Kid]], a sloppy yet inteligent inventor who finds himself hungry and unable to sell an invention. After being helped, Apple Kid gives Ness the Pencil Eraser, which allows Ness to bypass the Iron Pencil statue and enter Happy Happy Village. There, Ness finds Paula imprisoned in a cabin by the Happy Hapyist Cult, but is unable to open the cell she is in. Paula tells Ness that the leader of the cult, [[Mr. Carpainter]], possesses the key, and gives Ness the Franklin Badge necessary to confront him. Just outside, however, Ness discovers that [[Pokey Minch|Porky]] (who has been promoted to a "high position" of the cult) is working against him, and sends two cult members and a crow to attack Ness. Ness defeats the cultists, then confronts and defeats Carpainter, who agrees to free Paula. Together, Ness and Paula then enter a nearby cave and battle the [[Mondo Mole]], who guards the second sanctuary known as [[Lilliput Steps]]. Returning to Twoson, Everdread gives Ness a wad of bills, and Ness uses the money to help the [[Runaway Five]], a band performing at a theater and stuck there through a massive debt, become free from this debt, and the band out of gratitude helps the two arrive in [[Threed]].
Upon reaching Fourside, the group enters the Monotoli Building and find Porky again, now in cohorts with the city mayor, [[Geldegarde Monotoli]], who has been corrupted by the strange [[Mani-Mani Statue]]. Not wanting Ness to interfere, Porky forces the group out of the Monotoli Building and into the desert. Back there, they find Montague again in a much deeper hole, who explains in a distress that [[Guardian Digger|five large moles]] are infesting the mine. By defeating the moles, Montague gives Ness a diamond, which he uses to again help the Runaway Five out of debt. The Runaway Five then gives a final show alongside the singer [[Venus]]. Wishing to celebrate, the three of them visit a department store, only to have Paula kidnapped by the [[Department Store Spook]], who also creates a blackout in the store and causes monsters to appear. Ness and Jeff proceed to the spook and defeat it, but find that Paula is no longer with it and is now with Monotoli himself. After hearing various rumors that Monotoli visits the Fourside cafe often, Ness and Jeff arrive at the cafe, only to find a wounded Everdread, who had stolen the Mani-Mani Statue from Carpainter in Happy Happy Village, but found the statue stolen from him by Monotoli. Everdread tells Ness to check behind the cafe's counter, which warps them to a weird, hallucinogenic counterpart of Fourside known as [[Moonside]]. Navigating through the city, Ness and Jeff discover and destroy the Mani-Mani Statue, which causes Moonside to disappear.
Back in reality, Apple Kid once again calls Ness about a new invention called the yogurt dispenser, albiet it only is able to dispense
trout-flavored yogurt at this time, and sends it to Ness through Escargo Express. However, the delivery boy carelessly drops the dispenser in the desert, forcing Ness to return there yet again. There, he encouters a talking monkey that takes him to [[Talah Rama]], a wise sage that gives Ness the yogurt dispenser and teaches him PK Teleport. Ness and Jeff then return back to Fourside and gives the dispenser to Monotoli's maid, who allows Ness and Jeff to enter the Monotoli Building free of charge. Navigating the building, Ness and Jeff battle various [[Sentry Robot]]s before encountering a [[Clumsy Robot]], who, despite its weak appearance, is surprisingly powerful. Fortunately, the Runaway Five barge in and turn off the robot, and Ness and Jeff proceed to Monotoli's office. Inside, Monotoli cowers in fear due to losing the Mani-Mani Statue, and allows Paula to rejoin Ness. Monotoli also explains to Ness that the statue constantly told him to not allow Ness and his friends to enter [[Summers]], concluding that Ness should go to Summers in order to slow Giygas's plans. Although the Mayor tells Ness and his friends to use his helicopter to reach the city, Porky takes the helicopter for himself and escapes, leaving Ness with no way to get to Summers. Fortunately, Paula gets an instinct that they should return to Threed, and travel there with the Runaway Five. After returning to Threed, Jeff repairs the Sky Runner, and they set flight for [[Winters]] to discover the fourth sanctuary.
[[File:Mother 2 Summers.png|left|thumb|256px|Ness, Paula, Jeff and Poo travel through Summers]]
After awakening, Ness and the group return to Saturn Valley where Dr. Andonuts, Apple Kid, and various Mr. Saturns have created a new Phase Distorter, a time traveling device. Unfortunately, however, they find that the machine does not work, as it is lacking a critical component: Zyoxinite, a rare material only found in asteroid deposits. Recalling the asteroid in Onett, Ness returns to his home, only to find the area invaded by hordes of Giygas's soldiers and its inhabitants locked in their homes. Ness makes his way through the invaded town and reclaims the meteorite, then returns to Saturn Valley to give the material to Dr. Andonuts. After upgrading the machine, Andonuts explains to the kids that the machine cannot warp them to the past in their current form, as living things cannot withstand time travel and it would likely destroy their human bodies. To remedy this problem, Andonuts proposes to them to have their souls transplanted into robotic bodies, though not without warning them that he doesn't know whether or not the process is reversible. Despite this critical warning, Ness, Paula, Jeff and Poo are willing to take the risk.
Now in the form of robots, Ness and his friends use the Phase Distorter to travel to the [[Caves of the Past]], the lair of Giygas and his men. Upon reaching the end of the cave, they encounter Giygas and Porky, who informs the group that Giygas became so powerful that his mind was completely destroyed, referring to him as an "all-mighty idiot", and can only be contained within the ominous Devil's Machine. The group battle and defeat Porky, who then shuts off the Devil's Machine to release Giygas, trapping the kids in a chaotic dimension composed of his own indefinable being. Since Giygas is too powerful for Ness and his friends to overcome by fighting, Paula begins to pray, reaching out to the inhabitants of the Earth, including family members and friends, who all pray for their safety, and eventually, she reaches out to the player. The combined prayers of both Earth's inhabitants and the player reach Giygas and exploit his weakness, which turns out to be human emotions. Giygas begins to loose his grasp on reality and begins to deteriorate, causing Porky to panic and escape through time travel. Giygas then vanishes from existence, along with the damage he had done to Eagleland and the rest of the Earth. As a result, the souls of Ness and his friends depart from their robot bodies, travel back to the present and return to their respective bodies. After bidding each other farewell, the heroes return to their homes.
After the ending credits, Picky Minch comes to Ness's house in the middle of the night and gives him a letter from Porky that says "''Come and get me loser. Spankety, spankety, spankety!''", and the game ends with him and Ness pondering what has become of him.