Gregor Townsend's side scored four tries to secure a bonus point and could have had more with sharper finishing.
The world champions, despite making 10 changes after beating England, stretched their winning run over Scotland to 10 Tests by taking their chances at key moments.
After falling 14-0 behind through Embrose Papier and Evan Roos, Scotland hit back impressively as Matt Fagerson and Kyle Rowe crossed to level the scores at half-time.
A Ben-Jason Dixon yellow card handed Scotland a golden opportunity early in the second half, but they failed to capitalise before South Africa struck twice through Elrigh Louw and Damien Willemse. Zachary Porthen extended the lead before Scotland responded again with tries from Josh Bayliss and Ben White to set up a tense finish.
Scotland threw everything at the Springboks but couldn't find a leveller, with Jesse Kriel sealing a 42-24 victory late on.
Despite a spirited display and a record four tries against South Africa, Scotland were ultimately undone by missed opportunities with the Springboks taking.
Scotland captain Sione Tuipulotu told ITV: "We're really gutted to be honest.
"We battled back but the period after half time hurt us a little bit. I'm very disappointed at the moment but I'm proud of the group, I want us to keep our chins high.
"We had a lot of possession in their 22 but didn't capitalise."
When asked what his side need to improve upon after this evening's performance, Tuipulotu adds: "Execution when the pressure's high when you're away from home.
"The period after half time is going to hurt a little bit. We managed to wrestle back momentum but it wasn't enough. I think they showed a little bit better execution at the back end of the game that got them the win."
Looking ahead to Fiji next week, the captain says: "We need to travel well.
"There's been a lot of travel in the last couple of weeks, we need to rest up tonight and travel well tomorrow.
"Next week will be another physical test."