Karthikeyan grew up in Coimbatore in a motorsport family; his father was a former Indian national rally champion who won the South India Rally seven times. He attended the Elf Winfield Racing School in France and competed in a Formula Maruti national championship as a teenager before beginning a long climb through European junior series.
He won the British Formula Ford Winter Series in 1994, becoming the first Indian driver to win any championship in Europe. In 1996 he became the first Indian and first Asian to win the Formula Asia International series. He progressed through British Formula Three from 1998 to 2000, winning races at Brands Hatch and recording two wins at Spa-Francorchamps and the Korea Super Prix in 2000. Between 2001 and 2004 he raced in the Formula Nippon and World Series by Nissan championships in Japan, scoring wins and podiums, while also testing for Jaguar Racing (2001) and Jordan (2001) — the first Indian to test a Formula One car.
On 1 February 2005, Karthikeyan signed with Jordan for the 2005 Formula One season, becoming India's first Formula One race driver. His partner was Portuguese driver Tiago Monteiro. In his debut at the Australian Grand Prix he qualified 12th and finished 15th. His only championship points came at the chaotic 2005 United States Grand Prix, where most teams withdrew due to a tyre dispute and only six cars started; Karthikeyan finished fourth. He did not score points at any other race that season. At season's end Jordan was acquired and renamed Midland, and Karthikeyan departed. He subsequently served as a test and reserve driver for Williams in 2006 and 2007.
After five years away from Formula One, Karthikeyan announced in January 2011 that he would drive for the Hispania Racing Team (HRT), fulfilling his stated ambition of competing at the Indian Grand Prix in front of a home crowd. The HRT machinery was the slowest on the grid across both seasons.
In 2011, Karthikeyan set a statistical curiosity: with so few retirements at the Chinese and European Grands Prix, he twice set the record for the lowest-placed classified finisher in a Formula One event (23rd and 24th respectively). He was replaced mid-season by Daniel Ricciardo for most of the remaining rounds but returned for the inaugural Indian Grand Prix, where he beat Ricciardo by 31.8 seconds to finish 17th.
For 2012 he was confirmed alongside Pedro de la Rosa. The season's most significant incident came at the Malaysian Grand Prix, where Red Bull's Sebastian Vettel received a punctured tyre after contact with Karthikeyan's front wing while lapping him. Vettel publicly called Karthikeyan an "idiot," to which Karthikeyan responded by calling Vettel a "cry-baby" before later calling for a more mature resolution. Karthikeyan also had a dramatic retirement in Abu Dhabi when his steering broke and he was rear-ended by Nico Rosberg. He finished the 2012 season without points in 24th position in the championship.
HRT folded at the end of 2012, ending Karthikeyan's Formula One career. He totalled one championship points score across his entire F1 tenure.
Karthikeyan competed in the Japanese Super Formula series from 2014 to 2018. In 2019 he won the Fuji Super GT x DTM Dream Race at Fuji Speedway in a Super GT appearance for Nakajima Racing. He also made a brief foray into NASCAR in 2010, driving in the Camping World Truck Series at Martinsville Speedway where he finished 13th and became the first foreign-born driver to win the NASCAR Camping World Truck Series Most Popular Driver Award.
The Government of India awarded Karthikeyan the Padma Shri, the country's fourth highest civilian honour, in 2010. His career as India's trailblazing Formula One driver opened the path that led to a dedicated Indian Grand Prix on the calendar between 2011 and 2013 and directly inspired the Indian motorsport scene in the following decade.