McKidd was born and spent his childhood in Elgin, Moray, Scotland. He was a member of the local acting group the Moray Youth Theatre. As a teenager he was part of rock band Plan 9, touring the north of Scotland and enjoying some local success. Planning to study engineering he attended the University of Edinburgh but dropped out and instead enrolled at Queen Margaret College in Edinburgh to study drama. He also joined Edinburgh University's student theatre company, Bedlam Theatre.

McKidd's first professional role was in the television series Father Ted; he played Father Deegan in the 1996 episode "A Christmassy Ted". Some of his subsequent roles include Tommy in Trainspotting and Malky Johnson in Small Faces, with Iain Robertson. In 2004, he played James Hepburn, 4th Earl of Bothwell, the third husband of Mary, Queen of Scots, in the BBC mini-series Gunpowder, Treason & Plot.

He appeared in Kingdom of Heaven, the blockbuster movie directed by Ridley Scott, the 2002 film adaptation of Nicholas Nickleby and was also the voice of Jezz Torrent in GTA: Vice City. Others might know him from Neil Marshall's horror film, Dog Soldiers, as Pvt. Cooper. In the 2005 BBC drama, The Virgin Queen, he played Thomas Howard, 4th Duke of Norfolk.

In 1998, he again joined Robert Carlyleon-screen in the 4-part BBC2 series Looking After Jo Jo, playing the role of Basil, a drug dealing cohort of Carlyle's eponymous character. He was one of the stars of the joint HBO/BBC series Rome, where his portrayal of the soldier/politician Lucius Vorenus received critical acclaim.

Additional work includes his role in the Silence of the Lambs prequel Hannibal Rising (2007). In the fall of 2007, McKidd began his role as the lead character in the American science-fiction television series Journeyman on NBC. However, the show suffered from low ratings and only thirteen episodes have been produced. He has been rumored to be a possible Thor in the upcoming film. McKidd will appear in Season 5 of Grey's Anatomy as Owen Hunt, a military doctor on leave.