He made his debut as a film director in 1951 with the Afrikaans-language film Daar doer in die bosveld. He directed 24 films. He founded a company with Tommie Meyer but later they split up.

Uys received the 1981 Grand Prix at the Festival International du Film de Comedy Vevey for The Gods Must Be Crazy, and in 1974 he received the Hollywood Foreign Press Association award for best documentary for Animals Are Beautiful People.

Uys’s other well-known film was Funny People in 1977, which was a comedy in the same genre as Candid Camera in the United States, putting unsuspecting people in embarrassing positions. These included a talking postbox, with the voice of a man claiming to be trapped inside, who asks a passerby for help. When the passerby returns with his friends, the ‘talking’ postbox is silent, and his friends accuse him of being drunk. The sequel, Funny People II, was released in 1983, and features a young Arnold Vosloo who later found fame in Hollywood.

Jamie Uys’s most financially successful and well-known film is The Gods Must Be Crazy, a comedy first released in 1980. The film features a San farmer named N!xau in the lead role. Its plot concerns a Coca-Cola bottle that was thrown out of an airplane, fell into the Kalahari Desert and was found by a San tribe. As this was the only “modern” object in their world, it led to strife and it was decided that the bottle had to be returned to the Gods, who must have sent it in the first place. The character played by N!xau was given the task to return it. The movie generated extensive word-of-mouth success in Europe, Japan and North America, with the movie rights initially being sold to 45 countries. It spawned a less successful sequel, The Gods Must Be Crazy II.

Uys died of a heart attack in 1996 at the age of 74.