Mainwaring started his career with the Greenough Demons (Rovers) before being recruited by East Fremantle "The Sharks" in 1985. In his first season, he was a member of the Western AustralianState of Origin team and played in a Sharks premiership team.
He was a member of the West Coast Eagles' inaugural squad in 1987. He made his debut in round three that year, against Sydney at Subiaco and afterwards only missed one game for the season. and was named their best first year player. Mainwaring played for the Eagles on the wing and contributed greatly to their success, playing in both their 1992 and 1994 premierships. The image of him leaping with joy at the conclusion of the game, despite having a broken ankle, is one of the lasting images of the Eagles' first premiership. He played 201 games for the Eagles between 1987 and 1999, kicking 84 goals.
Mainwaring was an All-Australian in 1991 and 1996 and has been named on the wing in the West Coast Eagles' Team of the Decade in 1996, Team20 in 2006 and East Fremantle's Team of the Century in 1997. Whilst he never won the Club Champion award at the Eagles, he finished in the top 10 eight times, including placing third in both his debut and second years in the VFL and second in 1989, 1992 and 1996.
In 1997, he suffered a knee injury, which required a knee reconstruction and this put him out of action for the rest of that season. In 1998, while he was attempting to regain form, Mainwaring spent most of the season playing for the Sharks, before making his return to the West Coast side late that year. After another season in which he was in and out of the Eagles' side (and playing for East Fremantle), Mainwaring retired from AFL football.
He wore the Eagles' number 3 guernsey, a number which had only been worn by him and Chris Judd during the Eagles' history. The club retired the number for the following three seasons, until it was revived by Eagles' draft pick Andrew Gaff in 2011.
Mainwaring played another season for the Sharks in 2000, after which he retired.
After leaving football, Mainwaring took a job with Seven News. By 2007, he was reading the sport at the weekend, as well as reporting during the week. He also read the sport headlines during the news on Perth radio station Mix 94.5 from 5:30–9:00 am. In 2005 he was a Reporter of the Seven news desk. Since 2001 he was a member of the selection panel for the All-Australian team and the AFL Rising Star. He was married to Rani and had two children.
Mainwaring died in the early hours of 1 October 2007 after being rushed to Sir Charles Gairdner Hospital. Police and ambulance had been called to his address earlier that night after a complaint about a man yelling in the street. After Mainwaring refused assistance from the ambulance crew, he was released to the care of a neighbour. About an hour later, emergency services were called back to the property after he had convulsions and collapsed. Mainwaring reportedly told paramedics during the first visit that he had taken ecstasy and cannabis. Former Eagles player Ben Cousins spent time with Mainwaring on Sunday, 30 September 2007 and the coroner ruled that they had both been using cocaine. According to the WA State Coroner's report, Mainwaring had a seizure and died after overdosing on cocaine, rather than several different drugs as media reports originally claimed.
Mainwaring's memorial service was held on 8 October 2007 at Christ Church Grammar School, Claremont. About 1,200 people attended the service including 300 who watched on a big screen outside the chapel. A memorial match was played between his old club and rivals Fremantle in 2008, with the Eagles winning by 25 points. His two young children, along with the Matera trio also played in the match.
The West Coast Eagles decided that Mainwaring's number 3 jumper would be retired for the next three years as a mark of respect, the club named its Best Clubman award the Chris Mainwaring Medal in his honour, and the Roberts Rd wing of Subiaco Oval to be named The Chris Mainwaring Wing for all West Coast home games.