In 1952, a semester before Ernesto "Fuser" Guevara is due to complete his medical degree, he and his older friend Alberto, a biochemist, leave Buenos Aires in order to travel across the South American continent in search of fun and adventures. While there is a goal at the end of their journey - they intend to work in a leper colony in Peru - the main purpose is tourism. They want to see as much of Latin America as they can, more than 8,000 kilometers (5000 miles) in just a few months, and also bed as many Latin American women as will fall for their pick-up lines. Their initial method of transport is Alberto's ancient and leaky but functional Norton 500 motorcycle christened La Poderosa ("The Mighty One").
Their route is ambitious. They head south, aim to cross the Andes, travel along the coast of Chile, across the Atacama Desert and into the Peruvian Amazon and reach Venezuela just in time for Alberto's 30th birthday, April 2. Due to La Poderosa's breakdown, they are forced to travel at a much slower pace, and make it to Caracas in July.
During their expedition, Guevara and Granado encounter the poverty of the indigenous peasants, and the movie assumes a greater seriousness once the men gain a better sense of the disparity between the "haves" and "have-nots" of Latin America. In Chile, the pleasure travelers encounter a couple forced onto the road because of their communist beliefs. In a fire-lit scene, Ernesto and Alberto admit to the couple that they are not out looking for work as well. The duo accompany the couple to the Chuquicamata copper mine, and Guevara becomes angry at the treatment of the workers. There is also an instance of recognition when Ernesto, on a river ship, looks down at the poor people on the smaller boat hitched behind. Ernesto's connection to people in need is visceral and tactile throughout the film. It shows in the way he smoothes the forehead of a terminally ill woman who cannot afford a proper doctor.
However, it is a visit to the Incan ruins of Macchu Picchu that inspires something in Ernesto. He wonders how the highly advanced culture gave way to the urban sprawl of Lima. His reflection is interrupted by Alberto, who shares with him a dream to peacefully revolutionize modern South America. Ernesto quickly responds: "A revolution without guns? It will never work."
In Peru, they volunteer for three weeks at the San Pablo leper colony. There, Guevara sees both physically and metaphorically the division of society between the toiling masses and the ruling class (the staff live on the north side of a river, separated from the lepers living on the south). Guevara also refuses to wear rubber gloves during his visit choosing instead to shake bare hands with startled leper inmates.
At the end of the film, after his sojourn at the leper colony, Guevara confirms his nascent egalitarian, anti-authority impulses, while making a birthday toast, which is also his first political speech. In it he evokes a pan-Latin American identity that transcends the arbitrary boundaries of nation and race. These encounters with social injustice transform the way Guevara sees the world, and by implication motivates his later political activities as a revolutionary.
Guevara makes his symbolic "final journey" that night when despite his asthma, he chooses to swim across the river that separates the two societies of the leper colony, to spend the night in a leper shack, instead of in the cabins of the doctors. This journey implicitly symbolizes Guevara's rejection of wealth and aristocracy into which he was born, and the path he would take later in his life as a guerrilla, fighting for what he believed was the dignity every human being deserves.
"Wandering around our America has changed me more than I thought. I am not me any more. At least I'm not the same me I was." ~ Guevara at film's end
As they bid each other farewell, Alberto reveals that his birthday was not in fact April 2, but rather August 8, and that the stated goal was simply a motivator: Ernesto replies that he knew all along. The film is closed with an appearance by the true life 82-year-old Alberto Granado, along with pictures from the actual journey and a mention of Che Guevara's eventual 1967 CIA-assisted execution in the Bolivian jungle.