From Melbourne, Simpson played junior football for Eltham and the Northern Knights before being recruited to North Melbourne at the 1993 National Draft. He made his debut during the 1995 season, and won a premiership the following year, during which he was also nominated for the AFL Rising Star award. Another premiership followed in 1999, and in 2002, Simpson was named in the All-Australian team and also won North Melbourne's best and fairest award, the Syd Barker Medal. He was appointed club captain in 2004, and held the position until stepping down at the end of the 2008 season, with his span including a preliminary final in 2007. Simpson played his 300th game in 2009, the third North Melbourne player to do so, and finished his career towards the end of the season. He was appointed coach of West Coast in October 2013, replacing John Worsfold.
Simpson was appointed club captain in 2004, and he led the Kangaroos into the finals the following year.
In 2005, the skipper narrowly missed recording a fifth consecutive top-three finish in the club best and fairest. He finished 4th, one vote behind 3rd and 2 votes shy of second. That year he missed two games with a punctured lung, but he still tallied over 400 disposals for the season with his industrious playmaking style.
Round 5 2007, he racked up a career equalling high 41 disposals, including a goal, in the Roos 16 point win against Geelong at Kardinia Park. Weeks later, he played his 250th game against Carlton in a home game at Carrawa on the Gold Coast. North Melbourne won the game 22-13 (147) to 20-10 (130). Simpson had 20 disposals. At the end of the game, his team-mates celebrated his 250 milestone by chairlifting him from the field.
On November 5, Adam Simpson announced he was stepping down as captain but he would continue playing in 2009. Brent Harvey became the new captain.
In 2009 Adam Simpson along with Daniel Pratt admitted to making a YouTube video entitled “The Adventures of Little Boris”. The video was of a rubber chicken named Boris performing sex acts on a chicken carcass. This resulted in North Melbourne giving them fines of $5,000 each over their part in the sex video.
Simpson and Pratt were among seven Kangaroos players responsible for producing the film, which put a media spotlight on the club and AFL players in general over their attitudes to women.
Simpson retired during the 2009 season. With North Melbourne out of finals contention, Simpson announced his retirement on 27 July 2009. He played the last of his 306 games on Friday night against Carlton in round 18 at Docklands, July 31. He ended his playing career after 15 seasons in the same round he made his debut. Simpson played every game during the North Melbourne 1996 and 1999 premiership seasons, and during his career he missed seven games as a regular player. He was the third player to notch 300 games for North Melbourne. At the end of his playing career he was remembered as hard-at-the-ball and as a favourite son of North Melbourne Football Club.
West Coast Eagles appointed Simpson coach for the 2014 season. He replaced John Worsfold who stood down after a disappointing season in 2013. Simpson was selected ahead of applicants Scott Burns and Peter Sumich. In his first year as senior coach the Eagles finished 9th. The following year, Simpson and the Eagles surprised many commentators by their performance when the club finished 2nd at the end home & away rounds.
Prior to coaching the Eagles, Simpson began his coaching career as an assistant coach under Alistair Clarkson at Hawthorn in 2010, and he was the midfield & forward coach for the Hawks when the club won the Grand Final in 2013.