Karthikeyan grew up in a motorsport family; his father was a former Indian national rally champion who won the South India Rally seven times. Karthikeyan attended the Elf Winfield Racing School in France before returning to India to race in Formula Maruti at the age of 15.
He moved to Britain in 1994 and began building a European single-seater career. He won the British Formula Ford Winter Series in 1994 and the Formula Asia Championship in 1996, becoming the first Indian and first Asian to win the Formula Asia International series. Competing in the British Formula 3 Championship from 1998, he recorded two wins at Brands Hatch in 1999 before finishing fourth in the 2000 standings. He also competed at the Macau Grand Prix and won the International F3 race at Spa-Francorchamps.
In 2001, Karthikeyan became the first Indian ever to drive a Formula One car when he tested for the Jaguar Racing team at Silverstone in June, followed by a second test with the Jordan team later that year. He competed in the Telefónica and Superfund World Series from 2002 to 2004, finishing fourth in the championship in 2003. He took wins in the series at Valencia and Magny-Cours in 2004.
On 1 February 2005, Karthikeyan announced he had signed with the Jordan Formula One team, making him India's first Formula One race driver. His teammate was Tiago Monteiro. He completed the mandatory 300 km testing distance at Silverstone in February to obtain his superlicence.
Karthikeyan competed in all 19 rounds of the 2005 season. His sole championship points came at the 2005 United States Grand Prix at Indianapolis, which was heavily affected by a tyre controversy that caused all but three teams to withdraw. With only six cars running, Karthikeyan finished fourth, ahead of both Minardi drivers but behind Monteiro. His highest finish in a normal race was 11th. At the end of the season, the Jordan team was taken over and renamed Midland; Karthikeyan departed rather than agree to the reported $11.7 million seat fee the new management sought.
Following his Jordan stint, Karthikeyan was confirmed as a test and reserve driver at Williams for 2006 and 2007, though he did not race for the team.
During his years away from Formula One, Karthikeyan competed in A1 Grand Prix for Team India. In the 2007–2008 season he won two feature races, including the season finale at Brands Hatch from pole position, helping India to a top-ten championship finish. He also raced at Le Mans in 2009 with Team Kolles, finishing sixth in the Le Mans Series round at Spa-Francorchamps. A shoulder injury sustained in a fall just before the 24 Hours of Le Mans itself ruled him out of that race.
He made his NASCAR debut at Martinsville Speedway in March 2010, competing in the Camping World Truck Series for Wyler Racing. He finished on the lead lap in 13th and went on to win the series' Most Popular Driver Award for 2010, voted by fans, becoming the first foreign-born driver to win the award.
On 6 January 2011, Karthikeyan announced his return to Formula One with the Hispania Racing F1 Team (HRT). Competing in an uncompetitive car, he twice set records for the lowest finishing position in a Formula One event — 23rd at the 2011 Chinese Grand Prix and 24th at the 2011 European Grand Prix, the latter achieved because that race had no retirements. He was replaced mid-season by Daniel Ricciardo but returned for the Indian Grand Prix in October 2011, finishing 17th and outpacing Ricciardo by over 30 seconds.
Karthikeyan remained with HRT for 2012 alongside Pedro de la Rosa. The season produced several notable moments. In Malaysia, an opportunistic gamble on full wet tyres elevated him as high as fifth place before the safety car intervened, and he was running in a points-paying position before contact with Jenson Button's McLaren ended that prospect. At the Malaysian Grand Prix, a collision involving Sebastian Vettel prompted Vettel to call Karthikeyan an "idiot" on team radio, with Karthikeyan responding by calling Vettel a "cry-baby"; both drivers later called a truce. He finished the 2012 season 24th in the championship with zero points.
From 2014 to 2018, Karthikeyan raced in the Japanese Super Formula series. In 2019 he moved to Super GT, winning the Fuji Super GT x DTM Dream Race with Nakajima Racing and recording a podium with Modulo Epson NSX-GT. He ended his single-seater career in 2019.
The Government of India awarded Karthikeyan the Padma Shri, the fourth-highest civilian honor, in 2010.
Narain Karthikeyan's career represents a landmark in Indian motorsport. By reaching Formula One in 2005 he opened a door for subsequent Indian drivers including Karun Chandhok. His perseverance in navigating the financial and logistical challenges facing drivers from non-traditional markets, combined with the technical competitiveness of his performances at several European junior series levels, established him as a pioneering figure. His return with HRT in 2011 and 2012 showed continued commitment to Formula One long after most contemporaries had moved on.