Nettles attended St Austell School before studying history and philosophy at the University of Southampthon. He then attended the Royal Court Theatre.
Nettles had his first screen role in the film One More Time. The following year he played Dr. Ian Mackenzie in the period drama A Family at War, a role he continued until 1972.
Nettles later did five seasons with the Royal Shakespeare Company, appearing in plays such aa A Winter's Tale and The Merry Wives of Windsor.
In 1995, Nettles was approached to play Tom Barnaby in a new murder mystery series called Midsomer Murders. Midsomer Murders made him a household name across the world.
In February 2009, it was announced that Nettles would be leaving Midsomer Murders after two further series were made. His final appearance on-screen was on 2 February 2011, by which time he had appeared in 81 episodes.