Two-time world champion Zolani Tete was shot dead outside his home in Mdantsane, Eastern Cape, on Friday evening.
The 38‑year‑old was killed in what has been described as an ambush.
Officials said Tete was in his car waiting for the gate to his house to open when two armed suspects in balaclavas emerged from a vehicle and fired "multiple shots" at him and a 27‑year‑old female passenger, who remains in hospital.
South Africa's minister of sport, arts and culture, Gayton McKenzie, said: "South Africa has lost one of the finest fighters it has ever produced."
The two suspects fled the scene and a major investigation has been launched, McKenzie added.
Tete held the WBO bantamweight title from 2017 to 2019, as well as the IBF super-flyweight title in 2014.
He holds a Guinness World Record for the fastest knockout in a title fight, ending his match with Siboniso Gonya inside 11 seconds in 2017.
Tete last fought in July 2022, beating Briton Jason Cunningham by knockout in London, but it was later ruled a no-contest after he failed a drugs test.
He tested positive for anabolic steroid stanozolol and was given a four-year ban by the UK Anti-Doping Agency.
His ban ended on 29 July, 2026 and manager Mla Tengimfene confirmed he had been training for a comeback fight.
Tete had 29 wins in 34 fights, with four losses and one no-contest.