Two twenty-something men from Argentina, one a biochemist, the other a medical student close to graduation, set fourth one a cross-continent journey of South America aboard a 1939 motorcycle. Along the way, their eyes are opened to the changing landscape and particularly to the people they encounter, many of whom are poor and in dire circumstances. These encounters end up shaping their perspectives and changing their lives forever.

Ernesto Guevara is the 23 year-old student. He is awkward around women, honest to a fault, but is obviously a person of principle in the making. Alberto Granado is the biochemist and is much more at ease with himself. He fits in easily with the locals wherever they stop to stay with them. He dances well and totally throws himself into the moment to enjoy the good times with the people they meet. Ernesto, by contrast, is more of contemplative person and has firmer convictions. For example, he refuses to spend the $15 US a girlfriend has given him to buy her a bathing suit in the US, even though he and Alberto are usually starving and in need of shelter. He ends up giving the money away, much to the displeasure of Alberto.

Along the way, there is much swearing in this sub-titled film, as we see the duo wipe out on the motorcycle several times, encounter snow-filled roads in Chilie that force them to walk the motorcycle and generally argue over how to con or not to con people for food and shelter.

The film culminates with the pair arriving to volunteer at a leper colony. On one side of the river is the colony, and on the other side, the medical staff have their facilities and homes. Upon their first visit to the colony, the pair refuse to wear gloves, which is a strict rule, although the gloves are pointless since leprosy is not communicable. Soon, they are embraced by everyone, lepers and medical staff alike. They treat the patients like people, not like pariahs, and end up becoming totally accepted. In one scene, the nuns are serving everyone lunch except our heroes. When they enquire, they are told that only those who attend mass are allowed to be fed. Dejected, they leave the mess hall but find their patients approaching them with food behind the nuns backs.