Karthik steadily ascended the youth ranks. He made his Tamil Nadu under-14 debut in early 1999, and was promoted to the under-19 side at the beginning of the 2000/2001 season. He made his first-class debut for the senior side the following season.

Karthik made his first-class debut in late 2002 against Baroda as a wicket-keeper. He batted in five matches of the round-robin, scoring 179 runs at an average of 35.80 with a top score of 88 not out against Uttar Pradesh in his second match. Karthik’s form tapered off after this match, and he failed to pass 20 again during the season. He took 11 catches but, due to repeated wicket-keeping errors, he was dropped from the season’s final matches.

Karthik was selected for the India squad in the 2004 Under-19 Cricket World Cup in Bangladesh, and scored two half-centuries on an India A tour to Zimbabwe. He had a strong domestic first-class season in 2008–09. After starting the Ranji Trophy campaign with two single-figure scores, he scored 213 runs in partnership with Subramaniam Badrinath as Tamil Nadu defeated Uttar Pradesh by an innings. Karthik then scored 123 and 113 in consecutive matches against Baroda and Railways, before ending his Ranji Trophy campaign with 72 against Uttar Pradesh in the return match. He continued his strong run against Central Zone in the Duleep Trophy, scoring 153 (103 in one match). Karthik ended with 1,026 runs at 64.12 for the season, including five centuries and two fifties.

Karthik made his Test cricket debut in the fourth Test between Australia and India in Mumbai in October 2004, replacing Parthiv Patel (who was dropped for poor wicket-keeping). He scored 14 runs in two innings and took two catches, but was praised for his wicket-keeping on a pitch with variable bounce and spin on which 40 wickets fell in two days.

He played in only one match against England at Lord’s, scoring one run. Despite dropping England captain Michael Vaughan from Anil Kumble’s bowling, he eventually stumped Vaughan down the legside and took another catch. Karthik played in the 2004 ICC Champions Trophy against Kenya, taking three catches before being replaced on the ODI team by MS Dhoni. He did not play another ODI until April 2006.

Karthik had a chance to score highly in India’s two-Test tour of Bangladesh in December 2004. Against a team which had never won a Test, India swept the series and won both matches by an innings. Although his side exceeded 500 in both matches, Karthik scored only 25 and 11.

Dhoni scored 148 in an ODI against Pakistan, and he replaced Karthik for the three Tests at home against Sri Lanka. In ten tests since his debut, Karthik scored 245 runs for an average of 18.84 with one half-century and one other score above 25. He was selected as a back-up wicket-keeper and middle-order batsmen on the Test team in November 2006.

In April 2006, Karthik was recalled to the ODI team to give Dhoni a rest in the final ODI against England in Indore. He was not required to bat, as India cruised to a seven-wicket victory. Karthik was then reinstated as reserve wicket-keeper for the tour of the West Indies after scoring 134 runs for India A at 33.50, including a man-of-the-match 75 runs against the UAE. He had more opportunities at the international level later that year during the ODI tour of South Africa after Yuvraj Singh was injured. As a batsman in three of the ODIs, Karthik struggled with 42 runs at an average of 14.00 and a top score of 17 as South Africa took a 5–0 whitewash.

Karthik was married to Nikita Vanjara in 2007. Dinesh Karthik and Nikita divorced in 2012. He participated in the dance-reality show Ek Khiladi Ek Hasina with Nigaar Khan in 2008. Karthik got engaged to Indian squash player Dipika Pallikal in November 2013, and they married in traditional Christian and Hindu ceremonies in August 2015.

Dinesh Karthik’s 15-year-old career includes 94 ODIs, and 32 T20s. He has kept wickets for the Indian team in ICC events and crucial trophies, both ODIs as well as T20Is. Karthik averages best in T20s 33.25 with a strike rate of 143.52. While he was snubbed in ODIs after ICC World Cup 2019, Karthik is well in contention for ICC T20 World Cup 2020. He scored an unbeaten 31 to steer India to a six-wicket win in the Twenty20 International against South Africa, with one ball to spare, in 2007. Karthik then featured in the four-match ODI series against West Indies. After not batting in the victorious first match, he top-scored with 63 as a specialist batsman when India recovered from 35/3 to post 189 on a slow wicket at the Barabati Stadium in Cuttack. India won by 20 runs, giving Karthik his first man-of-the-match award. He was then selected for the series against Sri Lanka and the 2007 Cricket World Cup. Before their tour of England, India played a series of ODIs in Ireland against the hosts and South Africa. Karthik played in four matches, scoring 15 runs at 51.00 and keeping wicket in two matches.

Selected for the inaugural 2007 ICC World Twenty20 in South Africa in September 2007, he played in India’s earlier matches before being replaced in the semi-final and final by Rohit Sharma. Karthik remained on the Indian squad for the home ODI series against Australia, but his form declined in England. He played in only the final match in Mumbai, making a duck as India scraped home by two wickets.

Karthik played in the 2008 Indian Premier League as wicket-keeper for the Delhi Daredevils, scoring 145 runs at 24.16 with a strike rate of 135.51. His highest score was an unbeaten 56 to steer Delhi to a five-wicket win in a group match against the Mumbai Indians. In the 2009 Indian Premier League hosted by South Africa, Karthik played in each of Delhi’s 15 matches. He scored 288 runs at 36.00, passing 40 on three occasions and making 17 dismissals. Although Delhi topped the tournament’s pool stage, Karthik made only nine in the semi-final and Delhi were defeated by six wickets by the Deccan Chargers.

He had a lean Test series against Pakistan at home in late 2008. Karthik managed only 39 in two innings of the first two Tests, exceeding single figures only once. In the third Test in Bangalore, Sachin Tendulkar was injured; his replacement, Yuvraj, scored 170. Karthik, batting down the order, scored 24 and 52 in a high-scoring draw and kept the wickets because of Dhoni’s injury. In the first innings, Karthik was behind the stumps as India set a world record for the most extras conceded in a Test innings; the 35 byes were the secondmost in Test history.

He scored an unbeaten 117 against Kerala in the 2009 one-day tournament and was selected for the tour of New Zealand as reserve wicket-keeper. After watching the T20 and ODI series, Karthik played in the second Test when Dhoni was injured; he was criticised for dropping a number of catches.

In December 2009, Karthik was recalled to the ODI team during the Sri Lankan tour of India after Dhoni was banned after the second match for two matches because of low over rates. Karthik kept wickets in the next two matches, scoring 32 and 19 (unbeaten in both) and helping guide India to the target in successful run chases. He retained his place as a middle-order batsman in the fifth and final match when Dhoni returned after Tendulkar was rested and Yuvraj was injured, but the match was ended early due to an unsafe pitch.

He was bought by Kings XI Punjab in 2011 for $900,000, making him the second-most-expensive player on their squad. For the 2012 Indian Premier League, Karthik joined Mumbai Indians for a reported $2.35 million.

He was again bought by Delhi in 2014, by Royal Challengers Bangalore in 2015 and in 2016 by the Gujarat Lions, who retained him for the 2017 season. Karthik was named wicket-keeper of the IPL XI of the tournament in 2017 by CricBuzz. He was bought by the Kolkata Knight Riders for the 2018 IPL season (replacing Gautam Gambhir), and led the team to the playoffs. For his performance in the 2018 IPL season, Karthik was named to the Cricinfo and CricBuzz IPL XI. In 2020 Indian Premier League he continued his captaincy for Kolkata Knight Riders with winning 4matches and losing the opening match against Mumbai Indians. On playing against Mumbai Indians he gave his Captaincy to Eoin Morgan for the rest of the tournament.

On 10 December 2017 Karthik faced 18 deliveries without scoring a run against Sri Lanka, an ODI record. He was flown in for the third Test of India’s 2017–18 tour of South Africa to replace the injured wicket-keeper, Saha. The substitute, Patel, was included on the side before he injured his right index finger; Karthik began keeping the wickets on day four of the Test. Although he was on the squad for the limited-overs matches, he did not make the playing eleven (except for the final T20I, when he made a six-ball 13). Karthik was again named to the squad for the March 2018 Nidahas Trophy, Tri-nation series, after team regular (and wicket-keeper) Dhoni was rested. He played a match-winning knock of an unbeaten 29 off eight balls in the final of the tournament against Bangladesh. Coming to bat when India required 34 runs off the last two overs, Karthik’s assault (which included a six when requiring five runs off the last ball) won the match and the tournament.

Karthik was named captain of the India A cricket team for the 2018–19 Deodhar Trophy in October 2018. In October 2019, he was named to India C’s squad for the 2019–20 Deodhar Trophy.

In April 2019, he was named to India’s squad for the 2019 Cricket World Cup. On 6 July, in the match against Sri Lanka, Karthik played his 150th international match for India.