In the year 1862, amidst the turmoil of the American Civil War in the American Southwest, a trio of bounty hunters ambushes the notorious Mexican bandit Tuco Ramirez. However, Tuco manages to shoot them and makes a daring escape.
Meanwhile, the merciless mercenary known as "Angel Eyes", played by Lee Van Cleef, interrogates a former Confederate soldier named Stevens in hopes of uncovering the location of Jackson, a soldier who had stolen a hidden treasure of Confederate gold. In a turn of events, Stevens reveals the name "Bill Carson" in an attempt to bribe Angel Eyes. But when the conversation escalates, Angel Eyes kills Stevens and, captivated by the gold's allure, eliminates his own employer as well.
Tuco's luck changes when he is unexpectedly rescued from another gang of bounty hunters by The Man with No Name, an enigmatic drifter who Tuco nicknames "Blondie", portrayed by Clint Eastwood. Blondie collects a $2,000 bounty for Tuco, delivering him to a sheriff. Yet, just as Tuco faces execution, Blondie shoots the noose, freeing him. The pair then escape, splitting the bounty, as they repeat this scheme across various towns. However, Blondie soon grows tired of Tuco's incessant complaining and abandons him in the vast desert.
Driven by vengeance, Tuco tracks down Blondie, forcing him to march through the relentless desert until Blondie collapses from the heat. Fortune strikes when they encounter a runaway ambulance filled with deceased Confederate soldiers and a dying Bill Carson. Carson begs Tuco for assistance, promising a staggering $200,000 in gold buried in a grave at Sad Hill Cemetery. Tragically, by the time Tuco returns with water, Carson has passed away, but not before revealing the name on the grave to Blondie. They reluctantly pool their efforts, as Tuco knows the cemetery's location while Blondie remembers which grave to excavate.
Disguised as a Confederate soldier, Tuco takes Blondie to a nearby mission to recuperate, where he encounters his brother Pablo, who has become a priest. Their reunion is marred by hostility, leading to Tuco's swift departure with Blondie.
As they journey onwards, Tuco loudly expresses pro-Confederate views, only for the approaching soldiers to reveal themselves as a Union patrol. Consequently, both Tuco and Blondie find themselves imprisoned, where Angel Eyes has infiltrated the camp as a Union sergeant in his quest for Bill Carson. When Tuco, under the guise of Carson, is taken away for questioning, he is tortured until he divulges the cemetery's name. He is sentenced to hang, but knowing Blondie wouldn’t disclose the grave's name, Angel Eyes forcibly coerces him into his search.
Tuco manages to escape execution by eliminating one of Angel Eyes' henchmen and soon discovers that Blondie, Angel Eyes, and his gang have arrived in an abandoned town. They join forces to eliminate the gang, but Angel Eyes narrowly escapes. As they journey to the cemetery, the duo encounters conflict over a crucial bridge; Blondie opts to destroy it, hoping to disrupt the armies and clear their path.
While wiring the bridge with explosives, Tuco suggests they share their secrets in case one of them falls. Tuco shares the cemetery's name, and Blondie responds with the grave's name, "Arch Stanton".
After the bridge's destruction, Tuco seizes a horse and races ahead to Sad Hill, eager to find the treasure for himself. Blondie catches up just as Tuco starts digging, but soon, Angel Eyes appears as well. When no gold is found in the grave, Blondie admits to misleading them, suggesting instead a rock in the cemetery’s pavement bears the true name. Both men take the bait, and a Mexican standoff ensues, where tensions erupt as Angel Eyes draws first, but Blondie swiftly shoots him down, while Tuco realizes his gun is unloaded.
Blondie then reveals he had unloaded it prior in a cunning ploy. The gold lies beneath the grave marked "Unknown", resting beside Stanton's. Tuco hastily digs and discovers bags of gold but is soon met with treachery, as Blondie forces him into a hangman's noose tied to a tree. Bound at the neck, Tuco precariously stands atop an unstable grave marker while Blondie calmly commandeers half of the gold and rides away. As Tuco pleads for mercy, Blondie executes a calculated shot, severing the rope and sending Tuco crashing onto the mound of gold. Enraged, Tuco screams curses at Blondie, who fades into the horizon, leaving his former companion in a mix of gold and fury.
