Amidst the carnage of the Mexican Revolution, amoral outlaw Juan Miranda (Rod Steiger) and his bandit family roam the country looking for wealthy coaches to rob. After one lucrative raid, his path is crossed by John Mallory (James Coburn), an Irish explosives expert who has fled to Mexico with the intention of joining the revolutionaries. The chalk-and-cheese pair strike up an unlikely friendship, and while Juan initially thinks only of the money the pair can make, he is slowly drawn into his new partner's romantic political idealism.

Forming the second part of a loose trilogy with Once Upon a Time in the West and Once Upon a Time in America, Sergio Leone's final Western marked a further shift away from the ironic excesses of his earlier Spaghettis towards the more melancholy, reflective tone of his later work. An allegory of Italy's experiences during World War 2 and a commentary on the polarised extremity of the country's politics of the time of its production, this is both an ambivalent critique of violence in the name of ideology and a surprisingly moving examination of the nature of friendship and loyalty.