Dereck Chisora turned professional on 17 February 2007, scoring a second round TKO against István Kecskés.

After winning three more fights (all by decision), he came up against the toughest test of his career against fellow rising British heavyweight prospect, Sam Sexton. Chisora won the fight by stopping Sexton in the final 30 seconds of the final round. Chisora moved on from the win over Sexton by beating the American Shawn Mclean at the Grosvenor House hotel in Mayfair and then stopped the experienced Lee Swaby in 3 rounds at the York Hall. Chisora finished the year with a December victory over Neil Simpson at the ExCeL Exhibition Centre in London's Docklands leaving him with an 8-0 record at the end of his second year as a professional.

Chisora was suspended for four months for biting Paul Butlin during the fifth round of their 22 May 2009 contest at the York Hall in Bethnal Green. The incident was missed by the referee but TV replays proved conclusive and as a result Chisora missed out on his fight for a British title against Danny Williams. He was also fined £2,500.

Chisora went on to defeat Zurab Noniashvili on 9 October, winning by TKO in three rounds at York Hall and then on 20 January 2010 it was announced that he would get a second chance to face Danny Williams on 13 February 2010 after Sam Sexton was forced to withdraw injured from his match with Williams. Chisora welcomed the chance, saying, "It was my own fault the fight with Williams didn't go ahead, and I've been kicking myself ever since." Williams pulled out of the bout, however, and Chisora instead fought Carl Baker in an eliminator with the winner to face Williams. Chisora defeated Baker in the second round. On 15 May 2010 Chisora fought Williams for the British heavyweight title, which he won after stopping Williams in the second round. Chisora defeated a challenge from Sam Sexton by knockout in the ninth round on 18 September 2010. Chisora was scheduled to face the IBF, IBO, WBO and Ring Magazine heavyweight champion, Wladimir Klitschko on 11 December 2010, but Klitschko pulled out of the fight three days prior with a torn abdominal muscle. The fight was later rescheduled for 30 April 2011, but this was later cancelled so Klitschko could fight David Haye on 2 July.

On 23 July 2011, he fought Tyson Fury, who won the fight by 5 rounds on 2 judges' cards, and 7 rounds on the third judge's card.

On 3 December, Chisora faced undefeated Robert Helenius in Helsinki, Finland for vacant EBU heavyweight title. Helenius won by split decision. The decision was highly debated as most pundits and onlookers thought Chisora had done enough to get the decision. The Ring considered the outcome of the match "a gift", dropping Helenius' ranking from fifth to sixth challenger. Chisora complained afterwards demanding a rematch on a neutral territory.

Sources in Germany reported that he was likely to fight Ukrainian WBC Heavyweight Champion Vitali Klitschko on 18 February 2012 in the Olympiahalle, Munich, Bavaria. Later, on 12 December 2011, it was confirmed that Klitshko would be Chisora's next opponent. Chisora slapped Klitshko at the weigh in for the heavyweight title fight and has been widely criticised. Chisora is quoted as saying after the slap "I ain't come here to play games I come here to fight."

On 18 February, Chisora and Klitschko fought in Germany for the WBC Heavyweight Championship. Things got off to a rocky start when Chisora spat in Wladimir Klitschko's face during the introductions. After a close first round, Klitschko started to land his right hand in round two and continued to land clean power shots from a distance as the bout progressed. Chisora showed a good chin, and did the majority of his work to the body. The scores were 118-110, 118-110 and 119-111, giving a unanimous decision of victory to Klitschko.