Born in Burma, Michie was brought up in Kenya until he was twelve years old, when his family settled in Edinburgh, later sending him to study at college. At the age of nineteen, he worked his passage to Australia on a cargo ship, where he spent a year as a jackaroo herding cattle before returning to Scotland. He took a job as a stagehand at the Traverse Theatre in Edinburgh, where his interest in acting started. He returned to Kenya when he was 22, beginning his acting career in A Private Matter at the Donovan Maule Theatre, Nairobi in 1980.

Michie's first film role was in the 1989 film Conquest of the South Pole but his first leading role came in the film adaptation, Monk Dawson in 1998. Based on the Piers Paul Read novel, it gained a good reception from the critics despite only a short run at the UK box office. Michie played the character David Baird in John Madden’s 1996 film Truth or Dare starring Helen Baxendale and John Hannah.

Michie appeared in Moon and Son in 1992. In 1998, he was given a regular part in Taggart, playing DI Robbie Ross, a dedicated detective not afraid to go about things his own way and fly in the face of authority when he needs to.

Michie appeared in The Ruth Rendell Mysteries in 1994, co-starring Colin Firth. He played a pet shop owner, in the two-part episode "Master of the Moor".

In 1999, Michie starred alongside Richard Harris in To Walk with Lions, a film based on the life of George Adamson which featured Michie back in his childhood home of Kenya playing the wildlife Conservationist Tony Fitzjohn.

In 2008, Michie publicly backed the Scottish Labour Party in the run up to the Glasgow East by-election. However it later emerged Michie, in a report for the BBC's This Week programme the previous year, appeared to back Scottish independence, which the Labour Party officially opposes. Michie said, "An independent Scotland would find a new confidence. It would slow down the brain-drain that causes this country to lose so many of its most brightest and most skilled." The Labour Party subsequently issued a statement on behalf of Michie claiming he did not support independence.

Michie has three children with his partner Carol, a former Hot Gossip Dancer. He is a keen Swimmer and player of squash. His nephew is actor Jamie Michie, who has appeared in The IT Crowd, Game of Thrones and alongside John in one episode of Taggart in 2010.

From 2011 to 2013, Michie played Karl Munro in Coronation Street. His character was the partner of Stella Price (Michelle Collins). Since leaving Coronation Street, Michie has played a regular role in hospital drama Holby City, playing Guy Self and while continuing the role in 2014, he has also appeared in its sister show Casualty. Michie left Holby City in November 2016 after Guy hands in his resignation but returned in August 2017.

In August 2014, Michie was one of 200 public figures who were signatories to a letter to The Guardian opposing Scottish independence in the run-up to September's referendum on that issue.

In September 2017, his 25-year-old daughter, Louella, died at the Bestival music festival in Dorset. A 28-year-old man was subsequently arrested on suspicion of murder and was questioned by police.

Michie began his acting career on the stage and has appeared in several West End productions. Past roles include playing Arthur in Jean Anouilh’s comedy, Number One, at the Queen’s Theatre in 1984. He also played John in Noël Coward’s play, Easy Virtue, at the Garrick Theatre in 1988–89, before going on to play Walker in Andrew Davies’ Prin at the Lyric Theatre, 1989–90, directed by actor/director Richard Wilson. Michie was directed by Wilson twice more in Michael Wall's Women Laughing at the Royal Court Theatre and in Simply Disconnected at the Chichester Festival Theatre in 1996. He played Danny in Breed, a new play from emerging Playwright Lou Ramsden, staged at Theatre503 in 2010.