Uthappa made his One Day International debut in the seventh and final match of the English tour of India in April 2006.

Once a wicket-keeper batsman, his List A batting average of near 40 with a strike rate of approximately 90 has made him regarded as something of a limited overs cricket specialist.

He was selected in the 15-member squad of the Indian team for the 2007 Cricket World Cup held in the West Indies in March–April 2007.

He played in all three group games, but only scored 30 runs in total as India suffered a shock defeat to Bangladesh and a loss to Sri Lanka resulting in the team not qualifying for the Super 8 stage.

After Dhoni got out in the 47th over with the Indian score at 294, Uthappa kept a cool head to take India to the target with two balls to spare in a remarkable victory.

Uthappa also scored a crucial 50 against Pakistan in the 20–20 World Cup in South Africa in the year 2007, when India were tottering at 39/4.

After his impressive performance in the seventh season of IPL, he was selected to captain the India A team for its tour of Australia in July 2013.

[4] In November 2014, Uthappa was included into the Indian One Day International squad for the last two matches against Sri Lanka.

Against Kolkata Knight Riders, he stitched an unbeaten 123-run partnership with Dwayne Bravo, where he scored a run-a-ball 37 to steer Mumbai to an easy win.

[8] For the 2011 Indian Premier League, he was bought by Pune Warriors for a huge sum of US$2.1 million (approximately INR 9.4 crores) in the auction held at Bangalore.

[9][10] Even though IPL 5 was a disappointing one for Pune Warriors India, Uthappa remained their top scorer, scoring 405 runs from 16 games, which included a blistering 69 against the RCB.

The same happened in Season 6 of IPL: although the team's performance was poor, Uthappa managed to score 434 runs in 16 matches.

[16] He scored 63 runs from 44 balls in the Qualifier 1 against Delhi Capitals which helped Super kings to march towards the 9th IPL finals.

In the 2022 IPL Auction, Uthappa was bought by the Chennai Super Kings for his base price of ₹ 2 crores until being released ahead of the 2023 Indian Premier League.