The story takes place on an alien planet where a fleet of human ships crashed over a century ago. In the harsh conditions, the surviving humans are forced to depend on a special organism known as a plant, which provides them with food, water, and energy.
July, a large city, was completely wiped out, with a single man in rags standing above the wreckage. That man was Vash the Stampede. For the destruction of July and disappearance of all the inhabitants, Vash gained a bounty of $$60 billion (Double Dollars, the fictional currency). His bounty poster points out his distinctive appearance, and notes that Vash is a staunch pacifist.
The story begins in a diner where Vash is quietly enjoying his meal. A group of bounty hunters proceed to burst in and shoot up the place in an attempt to win the bounty. However, Vash easily avoids their attacks, and they soon run out of bullets. Meanwhile, two girls, Meryl and Milly, ask about Vash in a nearby bar, and set off towards him.
Back in the diner, the citizens have learned of Vash's identity, and decide to attempt to claim his bounty to repair their plant. Vash flees through the streets as Meryl and Milly arrive to find the city in turmoil. In desperation to capture Vash, the officials called the Nebraskas (father and son, both criminals). The Nebraskas attack Vash, with the surrounding citizens caught in the crossfire. Vash proceeds to rescue the citizens and defeat the Nebraskas. Meryl and Milly introduce themselves as agents of the Bernadelli Insurance Company and announce that the government has declared Vash the Stampede an Act of God and canceled his bounty. Vash turns in the Nebraskas for their bounty, and donates the money to the city. Meryl and Milly decide to follow Vash and monitor his activities.
The Sand Steamer, a massive locomotive used to travel between cities in the harsh desert environment, arrives in the city, and Vash boards. Meryl and Milly follow him. However, the Sand Steamer is attacked by the Bad Lad Gang with the help of the Kaito, the son of the man who designed the steamer. However, the boy cannot bring himself to allow the Steamer to be destroyed after the leader of the Gang, Brilliant Dynamite Neon Kou Rin, decides to crash the Steamer to open its safe. Vash and Kaito work to stop Brilliant, while Vash flashbacks to his time aboard a SEEDS ship, one of the ships in the original fleet, with Rem. After a duel with Brilliant, Brilliant is won over and stops the Steamer. After Vash leaves the Steamer, he reappears to help an old couple defend their plot of land, which they spent their lives to transform into a prosperous garden.
Vash, Meryl, and Milly later go to a town, where they play with the local children. While Vash is enjoying himself, he suddenly notices a mysterious man with blue hair and a white coat. The two telepathically communicate, where the man reveals himself as Legato Bluesummers, a servant of Knives, whom Vash had badly injured at July. Legato leaves behind a coin case containing 12 halved coins, telling Vash 12 assassins, each bearing one of the other halves of the coins, will come to attack Vash, and if Vash collects all 12, something will happen. Legato also leaves behind the head of the man who had previously repaired Vash's boots, and exits, leaving Vash to take the blame.
Vash is arrested and held in the jail, where he thinks back to his time with Rem, and remembers that Knives was the cause of the crashing of the fleet. Rem had sacrificed herself in order to save as many ships from destruction as possible. Vash is suddenly attacked by Gung-Ho Guns Number 1: Monev the Gale, first of the 12 assassins. Vash is forced to reveal the hidden gun in his left arm to escape, and in the resulting fight, loses his prosthetic arm. Many civilians are killed by Monev in the crossfire, and Vash begins to grow angry and unstable. When Vash finally defeats Monev, he puts out Monev's right eye with the barrel of his gun and nearly kills him while Monev begs for mercy, until he remembers Rem and spares the Burly Gung-ho Gun.
In the aftermath, Monev surrenders his coin and leaves. Meryl and Milly worry about Vash, and discover his body is mutilated and covered with scars from his battles. The three leave the city, where Vash finds Monev crucified, and the next Gung-Ho Gun waiting: E. G. Mine. Vash quickly defeats Mine and calls out to Legato, who is watching the battle, telling Legato that he will take the offensive.
Later, Legato thinks about Vash's challenge, and reveals his telepathic abilities to slaughter a gang of organ harvesters. At the same time, Vash is traveling by bus, where he discovers a mysterious figure with a large cross in the desert. The man introduces himself as Nicholas D. Wolfwood, a priest who works at an orphanage, and the two become fast friends. Meanwhile, Legato and the Gung-Ho Guns gather, demolishing the gang, but leaving some survivors, telling them to use their comrades bodies since there is so much money to be made in organ harvesting.
Vash arrives in the city to find the bloodstain of the slaughter, and is confronted by Gung-Ho Guns Number 3: Dominique the Cyclops. Vash defeats her, and Dominique surrenders her coin and commits suicide. Meanwhile, Wolfwood visits the local church, where it is revealed he is a Gung-Ho Gun known as Chapel. Doctor Conrad arrives and informs Legato and the Gung-Ho Guns that Knives' restoration is nearly complete.
Knives gains a new body from one of the plants, revealing he is in fact a plant. Vash senses Knives' restoration and immediately runs to confront him, telling Meryl and Milly to flee since his last meeting with Knives resulted in the July Incident. Legato tries to attack Vash, but is crushed by Knives, who is furious at Legato's independent actions, asking "who said you could kill him?" Knives then activates Vash's Angel Arm, a powerful weapon that a plant can create, to destroy the city, but Vash resists and directs his weapon upward, blasting a hole in the moon.
In the aftermath, Knives, Legato, and the Gung-Ho Guns retreat, while Vash disappears. From the incident, it is revealed that Vash is a plant. Vash disappears for the next two years, and the second part of the story, Trigun Maximum, begins