Makhaya Ntini was born in Mdingi, a small village in Cape Province which is near King William's Town (currently in Eastern Cape province). He was discovered by a Border Cricket Board development officer who was setting up a mini-cricket programme. Although Ntini was both too old and too big to participate in the programme, the officer, Raymond Booi noticed the bared-footed cowherd's enthusiasm and talent for bowling. He lent the 15-year-old Ntini a pair of plimsolls and arranged for him to participate in a net session in King William's Town. Ntini impressed Booi, who contacted the head of the development programme, Greg Hayes, and the pair placed Ntini in a junior cricket festival in Queenstown. For the festival, Hayes purchased Ntini his first pair of boots – but later had to give the young bowler instructions not to wear them indoors, or when herding cattle.
Two years later, he was selected to tour England with the South Africa Under-19 squad, and played all five of the youth internationals. England dominated both One Day Internationals (ODIs) during the tour, with the South Africans only managing to take one wicket across the two matches, which fell to Pierre Joubert. In the Test series, which England won 2–0, Ntini claimed nine wickets, the second-most by a South African bowler. His bowling was expensive, coming at a rate of 4.53 runs per over: more than any other South African with the exception of Mark Boucher, who is best known as a wicket-keeper. After two matches for Border against the touring Kenyans, Ntini made his first-class debut in November 1995, facing an England XI. He claimed two wickets in England's only innings as Border were beaten comprehensively.
In his debut season, Ntini claimed 17 wickets at an average of 37.05 in first-class competitions. His best performance in an innings came against Free State, when he claimed three wickets and conceded 49 runs (3/49) during his 17 overs. He once again toured with the national Under-19s in March and April 1996, touring India where he played three youth Tests, and one of the three ODIs. After claiming five wickets in the first Test, and none in the second, Ntini displayed his talent in the third match, taking 6/53 in the first innings and 3/48 in the second innings.
Ntini returned to the South African side for a Sharjah tournament in 2000. His improvement was clear as he bowled with greater control. In 2003 he became the first South African to take 10 wickets at Lord's Cricket Ground. Arguably his best performance, however, came on 12 April 2005, when Ntini took 13 wickets for 132 runs against the West Indies at Port of Spain. This remains the most wickets taken by a South African cricketer in a Test match. On 3 March 2006, Ntini also achieved the best bowling figures by a South African in an ODI, demolishing Australia with 6 wickets for 22 runs. A popular figure in South African sport, Ntini was voted their favourite sportsman in a research poll conducted by the South African Press Association.
Ntini went on to establish himself as South Africa's premier fast bowler and one of the leading fast bowlers in the world. In February 2009 he was ranked as the world's fifth-best Test bowler behind Muttiah Muralitharan, Dale Steyn, Stuart Clark and Mitchell Johnson, but had dropped to being 25th-best ODI bowler, according to the ICC rankings.
On 20 January 2007 Ntini dislodged Mohammed Sami to take his 300th test wicket, in his 74th test.
On 1 August 2008 he removed England opener Alastair Cook to claim his 350th test wicket in his 90th test.
On 17 December 2009 he played his 100th Test, becoming the only black South African cricketer to reach that mark. However, after already having lost his place in the ODI side, he was dropped from the Test side after poor performances against England.
Ntini retired from all forms of international cricket on 9 January 2011, in a T20 against India.
His career looked like coming to an early end in 1999 when Ntini was charged and then convicted of rape—though he was finally acquitted.
The case caused widespread controversy in South Africa with his conviction generating negative publicity in view of his status as the first black South African Test cricketer. Ntini maintained his innocence, was acquitted on appeal and successfully rebuilt his international cricket career. Ntini thanked Cricket South Africa for sticking by him.