Goalkeeper Ronwen Williams, Thapelo Morena, Dean Furman, Kamohelo Mokotjo and Lebogang Manyama came in as Bafana's changes from the loss against Zambia last month.
Harramiz Soares provided the hosts a big scare in the first ten minutes after heading a cross to the far post from the right-side onto the side-netting, after Manyama squandered a headed chance of his own earlier.
Bafana had a good chance to go in front before the midway stage with a gaping goal facing Percy Tau on the near side of the area, but the Belgian-based forward failed to capitalise as the visitors managed to clear.
Manyama, who was deployed upfront, went close to giving Bafana the lead from the head before the water break off a corner-kick taken by Tau, but the effort went over the top as frustration began to grow.
Sao Tome threatened again eight minutes before halftime as a floating ball from the left found a lurking Edmilson Viegas, who headed astray at the far post.
Bafana were out pumping in the second half, as a goalkeeping change for Sao Tome on 51 minutes had Nilson Taty replacing Adam Gamboa, who suffered an injury.
Taty was given a baptism of fire seconds from entering as Tau lined up from the penalty spot to rifle in the opener after going down in the six-yard area.
Themba Zwane should've handed Bafana a second with a free-header midway in the second half, but went wide as Mokotjo made way for the returning Bongani Zungu. Bafana missed another guilt-edge chance minutes later when a cross-field ball put Keagan Dolly level with Taty, who pulled off a point-blank save.
Mosa Lebusa could've grabbed his first international goal in the last 15 minutes with a header from Manyama's free-kick, but Taty came up with smart reflexes.
Bafana would get their second goal with a minute to go when Zungu leaped high in the area to send Dolly's cross over Taty, as it finished 2-0 in Durban.
South Africa: Ronwen Williams, Thapelo Morena, Innocent Maela, Mosa Lebusa, Thulani Hlatshwayo (c), Dean Furman, Kamohelo Mokotjo, Themba Zwane, Keagan Dolly, Lebogang Manyama, Percy Tau
Injured: Kermit Erasmus