The person presented with rare neurological disorder Guillain-Barre Syndrome soon after being given J&J's vaccine, after which the person was put on a ventilator and later died, senior scientists told a news conference.
"At the time of illness no other cause for the Guillain-Barre Syndrome (GBS) could be identified," Professor Hannelie Meyer said.
The person's age and other personal details were not disclosed for confidentiality reasons.
"The benefit of vaccination still far outweighs the risk," Boitumelo Semete-Makokotlela, chief executive of the South African Health Products Regulatory Authority (SAHPRA), told reporters.
Semete-Makokotlela said the regulator had assessed around 160 deaths since the COVID vaccination rollout started but had not seen a causal link to vaccination until now.
"In our context we have administered about 9 million (doses) of the Janssen (J&J) vaccine, and this is the first causally linked case of GBS."
South Africa's Health Minister Joe Phaahla told Thursday's news conference that as of mid-July there had been just over 6,200 "adverse events" reported to SAHPRA out of the more than 37 million COVID vaccine doses administered in the country, equivalent to 0.017%.
Around 46% of its adult population of 40 million is now fully vaccinated.
Europe's medicines regulator last year added GBS as a possible side-effect of AstraZeneca's COVID vaccine which, like J&J's, uses viral vector technology.
Last July, U.S. authorities added a warning to a factsheet for J&J's vaccine saying data suggested there was an increased risk of GBS in the six weeks after vaccination. At the time it noted 100 preliminary reports of GBS in vaccine recipients, including 95 serious cases and one reported death.
J&J did not immediately respond to an emailed request for comment. The company said at the time of the U.S. warning it was in discussions with regulators and the rate of reported cases of GBS in J&J vaccine recipients exceeded the background rate only slightly.