Duminy is a successful batsman generally occupying the top order, a skilled fielder and a useful change bowler. He became known during the South African under-19s tour to England in 2003 and in the 2003–04 domestic season, where he averaged over 72, two years after breaking into South Africa’s Western Province side. Though he bowls less frequently in One Day Internationals, he has also found success with the ball, making his ODI debut in 2004 against Sri Lanka.

Replacing injured vice-captain Ashwell Prince, Duminy made his Test debut against Australia at the WACA in Perth on 17 December 2008, scoring 50 not out in the second innings and putting on an unbroken century partnership with AB de Villiers. His performance was lauded by numerous critics, including Peter Roebuck. In the next Test match Duminy combined with the tailenders to score his maiden Test century, making 166 runs. South Africa were more than 200 runs in arrears when they lost their seventh wicket in the first innings. In the process, he and Dale Steyn put on 180 and surpassed Graeme and Peter Pollock’s South African ninth wicket partnership record against Australia. South Africa ended with a 62-run lead and converted it into a nine-wicket win. This sealed the series, the first time that South Africa had won a Test series in Australia, and Australia’s first home Test series loss in 16 years. He also took his first Test wicket in the 3rd Test of the tour.

Duminy played in the Indian Premier League in 2009 after the Mumbai Indians franchise acquired him for US$950,000. He scored two half-centuries in the tournament. Duminy went on to play for Sunrisers Hyderabad and Deccan Chargers and was named the captain of Delhi Daredevils in 2015. He was bought back by Mumbai Indians for the 2018 season and later released ahead of the 2019 IPL auction.

During 2011 ICC Cricket World Cup, Duminy became the second batsman after Adam Gilchrist to be dismissed for 99 in a World Cup match.. During 2015 ICC Cricket World Cup, Duminy became the first South African to take a hat-trick in a World Cup match. He dismissed Angelo Mathews with the last ball of an over, then dismissed Nuwan Kulasekara and Tharindu Kaushal with the first two balls of his next over. In that World Cup he along with David Miller set the record for the highest fifth wicket partnership in ODI history, the pair scoring 256 runs in an unbeaten partnership. On 5 November 2016, Duminy scored his fifth Test century during the first Test against Australia at Perth, in a partnership of 250 runs with Dean Elgar, at the time the second highest partnership for South Africa against Australia.

Duminy is married to Sue with whom he has two daughters. He is a Christian, and returned to religion in 2013 during an international tour of Sri Lanka.

In October 2017, Faf du Plessis suffered an injury during the third ODI against Bangladesh and ruled him out of the T20I series. Duminy replaced him as T20I captain for that series

He also played in the Pakistan Super League in 2018 for Islamabad United whom he captained to the league title. He captained Winnipeg Hawks to the 2019 Global T20 Canada title, with Duminy named Player of the Tournament during which he was the leading run scorer. His final T20 tournament was the 2019 Caribbean Premier League when he played for Barbados Tridents.

In April 2019, he was named in South Africa’s squad for the 2019 Cricket World Cup. Duminy retired from the game after playing his team’s last group stage match against Australia.