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After all the crazy adventures and tragic conflicts, Vash finally meets up with his brother Knives, but it is not a pretty sight as he recalls the history between them in the past 130 years. As advanced forms of the Plants, Knives had been intent on destroying the human race, while Vash had heeded Rem's philosophy of saving everyone. Knives proves to be Vash's most difficult opponent of all as he is equipped with the same weapons as Vash. The survival of the planet lies on the fate of the battle.
Vash wakes up after a deep slumber following the events from the previous episode. As Milly takes on local jobs to support everyone, Meryl attends to Vash's recovery, and takes on a job or two herself. But one day the town folk are upset when they learn that the recovering guy is Vash the Stampede, and attempt to lynch him for all the recent death and destruction to their families and neighboring towns.
Vash rests in a seemingly peaceful town of LR, thinking about Wolfwood and what to do next. But the peace is interrupted by Midvalley the Hornfreak who attacks and repels with his saxophone's sound waves. But Midvalley isn't the only enemy involved, as town folk are being forced in the line of Midvalley's fire by Legato's special manipulations. Vash confronts Legato, who is more than ready to die by Vash's hands, if it means pushing Knives' agenda, and threatening more innocent bloodshed along the way.
Wolfwood struggles with his past life, and the consequences and sins gathered from traveling with Vash. He encounters a man from his past who releases him from the contract linking him and Knives. Wolfwood decides to have a duel with Vash one last time, but they are interrupted by the sniper Caine the Longshot. While Vash goes after Caine, Wolfwood goes after his protege Chapel the Evergreen in a duel to the death.
Vash, Wolfwood, and the insurance girls arrive at a city but the townsfolk won't let them through. They end up befriending a boy who takes him back to a hideout area where a bunch of orphaned kids reside. The kids relay the story of how one day their parents just stood up and left their villages in a zombie-like trance. To make things worse, some sand worms have run wild, attacking both the orphans and the city folk, and another Gung-Ho Gun is revealed.
On the old Project Seeds ship, Vash and Wolfwood feel the wrath of Leonof the Puppetmaster and he not only sends out puppet zombies, but he has brought two Gung-Ho Guns who kill and destroy many citizens of the floating ship, and threaten to bring the whole station down in a blaze of glory.
With Jacqueline the Typhoon (a literal one this time) striking New Oregon, many folks stay indoors to weather the storm, but not Vash the Stampede, who hitches a ride on a piece of scrap metal that hurls him up into the skies. He ends up on a floating fragment of one of the Project Seeds ships where some of his friends, whom he hasn't seen in 13 years, reside. But they are strongly suspicious of Wolfwood who has tagged along, and things get dangerous when crew members get murdered, and one of the folks is kidnapped.
With Vash surfacing again in towns like Little Jersey, Meryl's boss gives Meryl the assignment of tracking him again, and she is eager to get back into it. Vash and Wolfwood make their way to New Oregon where a bitter feud is going on between the Polo and Fris families over a satellite facility. Meryl and Milly ride a sand steamer to New Oregon when it gets hijacked by the Fris family and crashed right into town. The Fris gang have captured a Polo son hostage; but with the Polo head far away, Vash is going to try to rescue him.
Wolfwood arrives at a town where folks are trying to clear out as they have heard Vash the Stampede is coming. As he visits a bar, he encounters a young woman named Lina who gets harassed by a guy who claims to be Vash until some other guy named Erics begs him to stop. Erics even volunteers to strip naked and beg like a dog to save Lina, but when he actually does so, Wolfwood has an idea who Erics really is. And when Lina gets abducted, they go on a rescue mission.
Some years ago, Vash and his brother Knives were traveling companions, but instead of the planet with all the months for cities, they were in outer space. The history between Vash, Knives, and this mysterious woman named Rem Severem unfolds, revealing some of the brothers' current motivations.
After Vash's encounter with Dominique. Vash receives a challenge from Legato to fight in Augusta city. Vash arrives and clears out the town, only to face two new Gung-Ho Guns: the spiky shooter E.G. Mine and the sword-wielding samurai Rai-Dai the Blade. Vash is forced against his will to reveal the third of his weapons, the devastating Angel Arm.
At the city of Jeneora (January) Rock, a bunch of outlaws representing the Roderick Thieves visit a pub but get into trouble when they encounter Legato, who can manipulate people's limbs telepathically, like making people shoot each other. Outside the city, the Roderick gang try to fight Legato but the Gung Ho Guns arrive and kill off half of the gang with unnatural weapons and techniques. After carrying Meryl and Milly across the desert, Vash enters the bar for a drink but only sees bloodshed. Suspecting Legato, he searches town and the nearby area, and encounters the deadly and beautiful Dominique the Cyclops, who moves so quickly as to appear to teleport.
Outside of the town of Promontory, an old couple try to protect a lush piece of island in an otherwise arid world. They ask Millie and Meryl to help guard them as the final deed transaction is taking place soon, but the couple's rivals want the land, and have even hired the couple's son to kill the family. With Vash asked to take a break, Milly and Meryl are up for a big challenge as they face more of the Nebraska family.
Meryl recaps the situation on Vash so far with a letter to her Insurance company where she highlights some of Vash's feats of heroism only to be coupled with feats of silliness or further destruction.
Vash encounters Legato Bluesummers for the first time and is warned about his impending doom. In the town that Vash visits, a shoemaker is killed, and Vash somehow gets framed for it. While Vash is in Jail, Legato hires a guy named Monev the Gale to kill Vash. But Monev faces the consequences of an enraged Diablo Vash when Monev goes after innocent people.
Milly goes into a caravan town to get some groceries and meets up with Wolfwood. They find a dancer girl who is trying to run away, and help her out. Later the girl meets up with her friend. Meanwhile, Vash is hired to go after the caravan owner's son who wants to leave the business. But the son turns out to be the girl's friend, and things get complicated when other caravan operatives reach Milly and the couple, and Vash given a directive to kill.
In May City, Vash quickly becomes friends with the local kids, letting them wrestle around with him, except for one kid, Neil, who seems rather sullen. Vash tries to help Neil and ends up seeing Wolfwood at the restaurant where Neil's mom works. Wolfwood recruits Vash to participate in the town's quick draw contest to raise money for Neil's family. But as the contest unfolds, Vash learns that it's not just shooting a line of bottles, but he has to duel. On top of that, Wolfwood gets entered into the contest and gets persuaded by the mayor to try to kill Vash for the reward money in order to save Neil's mom who is held hostage.
Vash and the insurance girls ride a bus through the desert to May City. Vash notices a glimmer in the distance, and it turns out to be a priest named Nicholas D. Wolfwood. After picking him up, the bus is attacked by some mechanical spiders. Vash and Nicholas go off to fight them, and Vash learns there is more to Wolfwood than a humble man of the cloth.
Vash and the gang must deal with a hijacking situation from B.D. Neon and the Bad Lads. With one officer down, there isn't much negotiating room as the captain turns up the heat to drive the sand steamer towards its doom. Vash learns of Kaite's past and works out a plan to save the steamer.
Making an escape from the grateful town, Vash boards a sand steamer and volunteers his guardian services in exchange for the fare. He finds a kid (Kaite) near his room, and offers food, but as he shares his meal, he gets drugged and goes unconscious. Kaite lets an outlaw gang called the Bad Lads into the steamer, and the ship gets hijacked! Their leader, B.D. Neon, wants to get the ship's treasure even if it means crashing the entire ship into pieces.
A steamer ship arrives at the town that Vash saved, with a lady so beautiful that Vash acts like a lap dog around her, much to Meryl's chagrin. Her name is Elizabeth, and she is in charge of repairing the Plant. She easily gets Vash to serve as a bodyguard, but Elizabeth isn't just an innocent cutie.
Some bounty hunters attack another bar in an attempt to hunt down Vash the Stampede. Vash appears to be covered in blood but not really, as he easily disarms the hunters but still proves to be a bumbling fool in front of the insurance girls. The town is grateful but then immediately turn on him for the much needed reward money. As they run all over town, the villagers have caught him in a building, but the sheriff hires the Nebraska Brothers, one of whom has a fist capable of leveling an entire building, villagers and all. Meryl realizes Vash could be a hero after all as Vash sticks out his neck to try to save the villagers.
A group of outlaws rush a bar and take the mayor's daughter and the insurance girls hostage. As the mayor and the sheriff ponder strategies to recover her, Vash casually walks into the place and somehow avoids getting shot up by the outlaws. He learns from the head outlaw guy that the mayor is known as Grim Reaper Bostalk, with a corrupt past. Vash sympathizes and tries to negotiate, but Bostalk and the Sheriff sends for a group of shady mercenaries in a rescue attempt.
Vash visits a town, looking for Frank Marlin, a gunsmith who could help him tune up his pistol, but he ends up meeting a middle-aged man and shares drinks with him throughout the day. The town has no sheriff since Frank Marlin had provided everyone with guns to defend themselves, but that was a while ago, and there is no need since nothing happens around town. That is, until some outlaws decide to stage a robbery there under the name of Vash The Stampede.
Meryl and Milly reach a town that is half covered in sand. Hardly anyone lives there anymore except for a guy named Cliff Schezar who befriends the girls, offering them water and housing them in his luxurious mansion. Vash, who Milly thinks is an imposter because of his tomfoolery, is hired to protect Cliff who owns the local water works, and a female companion named Marianne. But after Vash goes after some intruders outside, he and the girls discover that Cliff and Marianne are not who they seem to be.
The rumors fly that Vash the Stampede, an infamous outlaw worth $$60,000,000,000 dead or alive, is in town. Wherever he goes, destruction is sure to follow. Meryl Stryfe and Milly Thompson, representing the Bernadelli Insurance Company, are charged with tailing Vash wherever he goes, but first they have to figure out who this legendary Vash is from the conflicting descriptions. They meet a goofy blond guy with a red coat, but immediately dismiss him as a possibility. Then a woman named Ruth Loose pursues a group of bounty hunters whose boss could be Vash. As Meryl and Milly track Ruth, they get into some trouble, but are rescued by an unlikely hero.
