Coulthard began karting at age 11 after his father, a Scottish National Kart Champion, gave him his first kart. He won multiple Scottish junior karting titles and became the first recipient of the McLaren/Autosport Young Driver of the Year award, which included a McLaren Formula One test. In 1991, racing for Paul Stewart Racing in British Formula Three, he took five victories and finished second in the championship behind Rubens Barrichello. That year he also won the Macau Grand Prix and the Masters of Formula Three. He contested the International Formula 3000 series in 1992 and 1993, finishing third in his second season with Pacific Racing.
Coulthard had been employed as the Williams test driver throughout 1993 and 1994. When Ayrton Senna died at the 1994 San Marino Grand Prix, he was promoted to the race seat. He scored his first podium with second place in Portugal and finished eighth in the Drivers' Championship. The following year, at the Portuguese Grand Prix, he took his maiden Formula One victory after leading the majority of the race from pole position. He finished the 1995 season third in the championship alongside Damon Hill.
Coulthard joined McLaren for 1996, partnered by Mika Hakkinen. His first seasons with the team were inconsistent, but the arrival of the dominant McLaren-Mercedes package from 1998 brought sustained success. In 1998 he won the San Marino Grand Prix and helped McLaren secure the Constructors' Championship, finishing third in the Drivers' standings.
His best season was 2001, when he won in Brazil and Austria and finished second in the Drivers' Championship, 58 points behind champion Michael Schumacher. He was awarded the Hawthorn Memorial Trophy — given annually to the most successful British or Commonwealth driver in Formula One — in 1998, 2000, 2001, 2002, and 2003, a record run.
Coulthard won the Monaco Grand Prix in both 2000 and 2002. His nine seasons at McLaren produced 12 of his 13 career victories. He was replaced at the end of 2004 by Juan Pablo Montoya.
Coulthard joined Red Bull Racing for 2005 after the energy drink company acquired the Jaguar team. The car was initially uncompetitive, but at the 2006 Monaco Grand Prix he secured Red Bull's first podium, finishing third. He remained with the team through the 2008 season, announcing his retirement before the British Grand Prix. In Canada that year he took his final podium, finishing third. His last race was the Brazilian Grand Prix, where his car was decorated in the colours of the Wings for Life spinal injury charity.
At the 1998 Belgian Grand Prix in wet conditions, Coulthard was involved in a multi-car collision on the first lap. After the race was restarted, he was later hit by Michael Schumacher while being lapped, leading to an angry confrontation in the pit lane. Coulthard later admitted the accident was his mistake. Earlier in 2000, he survived a plane crash near Lyon when the Learjet he was travelling in lost an engine; the two pilots died.
At the 1995 Argentinian Grand Prix, Coulthard and Schumacher were both disqualified for fuel irregularities, though both results were later reinstated on appeal. In the opening race of the 1997 season in Australia, Coulthard scored his second career victory. At the start of the 1998 Australian Grand Prix, a pre-race team agreement meant Coulthard let Hakkinen past to win despite leading, creating significant public controversy.
Coulthard joined the BBC as a Formula One pundit and commentator after his retirement, working alongside Martin Brundle. When Channel 4 took over terrestrial broadcasting rights in 2016, he moved with the production, co-owning Whisper Films which produced the Channel 4 coverage. From 2022 he worked with the Nordic streaming service Viaplay as a Formula One expert alongside Mika Hakkinen and Tom Kristensen.
He contested three seasons of the Deutsche Tourenwagen Masters with Mucke Motorsport from 2010 to 2012 before retiring from motorsport. He twice won the Race of Champions Drivers' Cup, in 2014 and 2018. In 2019 he became president of the British Racing Drivers' Club, owner of Silverstone Circuit. He was appointed MBE in the 2010 Birthday Honours for services to motorsport.