John Thomson and long-time collaborator Mark Shirrefs met while undergraduates at the Victorian College of the Arts Drama School in 1976. They worked separately in the performing arts for some years, specialising as comedy directors and writers. Thomson worked (with American script-writer Gerry Wollery) on the initial adaptation for large ensemble comedy film Scavenger Hunt (1979) and both directed and wrote (with script-writers Lance Curtis, Neill Gladwin, Stephen Kearney, Geoff Kelso, and Mark Little) the skit-based short film Tennis Elbow (1982).

Shirrefs and Thomson completed the Swinburne Institute of Technology postgraduate film course in 1982 and 1986 respectively. Their first collaboration was 1990's Let The Blood Run Free, a satire of day-time hospital soap operas, which had begun life as an improvished stage show in Melbourne but was brought to television after the intervention of Ian McFadyen. Thomson and Shirrefs are, however, best known for their extensive body of work in children's science-fiction and fantasy television, which began in 1989 with The Girl from Tomorrow for Channel 9. It won an AWGIE Award for best original children's script and sold in over sixty countries. The 1991 sequel series, Tomorrow's End, won an ATOM Award and had similar commercial success. Both series were novelised and published by Hodder and Stoughton.

In 1995, Thomson and Shirrefs developed Spellbinder, another children's science-fiction/fantasy series, for Channel 9. A co-production between Film Australia and Polish Television, it won two ATOM awards, an AWGIE award, and an AFI award. Two Spellbinder novels were published in 1995. Spellbinder was followed by a sequel, Spellbinder II: Land of the Dragon Lord.

Their subsequent collaborations include scripts for Mission: Top Secret, Pig's Breakfast, and Scooter: Secret Agent.

Thomson has written scripts independently of his long-time collaborator, including for The Sleepover Club and Outriders.

Thomson has also continued to work as a director, including on American film Candy the Stripper (a romance set in New Orleans) and Australian TV series Bingles, his own Let The Blood Run Free, Wedlocked, and Full Frontal. In Bingles, he was continuing the association with Ian McFadyen that had begun with Let The Blood Run Free. He also worked as script editor for the Australian film Crackers.