The winger set up the opening strike for Diafra Sakho after 12 minutes and then had a shot saved shortly before half-time, which rebounded off home defender Thamsanqa Mkhize for an own goal.
The win put Senegal on 11 points in the standings, out of the reach of the rest of the teams and ensures a second appearance at the World Cup finals after they reached the quarter-finals in Japan and South Korea in 2002.
Friday's match was a replay after South Africa had beaten Senegal 2-1 at the same venue a year ago, only for FIFA to find that the outcome had been manipulated by Ghanian referee Joseph Lamptey, who has since been handed a life ban.
Mane had been an injury doubt for the qualifier up until last week when he made an quicker-than-expected recovery from a hamstring injury to return for his club Liverpool in Saturday's Premier League win over West Ham United.
He played the full 90 minutes for his country on Friday, setting up the opening goal with a sublime pass behind the South African defence for Sakho to net his second in successive qualifiers after also scoring last month against Cape Verde.
South Africa could have equalised just before the half hour mark when Lebogang Manyama struck the upright as the home team surged forward in a bid to get back into contention and keep alive their slim hopes.
But there was a killer blow on the counter attack after 38 minutes when Mane broke through the middle to shoot at goal, holding off the challenge of Mkhize.
His shot was saved by South Africa goalkeeper Itumeleng Khune but rebounded off the head of the stumbling Mkhize to roll back in the opposite direction for an unfortunate own goal.
Mane continued to prove a handful for the home defenders in a less frenetic second half as Senegal held onto their lead and ensured World Cup qualification.
The two sides meet again in Dakar on Tuesday in their final group game but it will be only cause for home celebrations.
(Reporting by Mark Gleeson; Editing by Christian Radnedge)
