Recalled captain Siya Kolisi was among the try scorers as South Africa outmuscled Wales to win the third Test 30-14 in Cape Town on Saturday and seal a 2-1 series victory.
All three Springbok tries stemmed from physical strength and after Wales came within three points early in the second half the hosts pulled away for an ultimately convincing triumph.
Fly-half Handre Pollard, who scored 20 points including three conversions and three penalties, and hooker Bongi Mbonambi were the other try scorers for South Africa, who led 17-8 at half-time.
Despite the series loss, gutsy Wales will leave the republic with a greatly enhanced reputation after putting behind them a humiliating home loss to Italy in the Six Nations in March.
Success for South Africa halted a run of series victories by northern hemisphere teams with France winning in Japan last weekend, and Ireland in New Zealand and England in Australia earlier on Saturday.
"It has been a tough series, exactly what we needed to start our season," said Kolisi, after the Cape Town victory followed a 32-29 first Test win and a 13-12 second Test defeat.
"The coaching staff had a plan from the beginning and they stuck to it. A lot of players had opportunities and that is important.
"Today we were playing in a final and the players pitched up. We really appreciate the people who have supported us."
Wales fly-half and captain Dan Biggar said: "I'm massively proud. It has been the easiest job in the world with this group.
"Congratulations to South Africa -- in the last 20-25 minutes they just squeezed us and we could not get our hands on the ball.
"We have shown on this tour that we are good enough to compete. Hopefully we will enjoy our off-season and come back strong."
Wales suffered a severe blow just before the kick-off when No. 8 Taulupe Faletau was injured while warming up and had to be replaced by Josh Navidi with Taine Basham promoted to the bench.
- Etzebeth cheered -
The biggest pre-match cheers were reserved for Springbok lock Eben Etzebeth, who ran onto the field ahead of his teammates in recognition of him winning his 100th cap.
After the match, Etzebeth said: "It is unreal, a special day. We approached it as a final, the guys were awesome."
South Africa started superbly, dominating possession as they camped in the Wales half and Pollard slotted a fifth-minute penalty from close range to open the scoring.
Intense pressure from the home team close to the tourists' tryline followed and they stretched the lead to 10 points by the 16th minute as Pollard dived over close to the posts and converted his try.
Almost immediately, veteran Alun Wyn Jones extended his world record number of caps for Wales to 153 when he come on for injured flanker Dan Lydiate.
The visitors got back into the match at the end of the first quarter when patient handling culminated in flanker Tommy Reffell taking a pass from winger Josh Adams and scoring an unconverted try.
Star Springboks winger Cheslin Kolbe then had to leave the field injured with veteran Willie le Roux coming on and forcing a backline reshuffle that included full-back Damian de Allende moving to centre.
English referee Matthew Carley warned Wales several times to cut out infringements that led to eight penalties being awarded against them by the 25th minute.
South Africa got a second try three minutes before half-time as Mbonambi celebrated his 50th cap by scoring a pushover try off a lineout and Pollard converted for a 17-8 half-time advantage.
Two successful Biggar penalties reduced the gap to three points before Kolisi, one of 10 changes to the team beaten in Bloemfontein last weekend, barged over for a third try.
Pollard converted and slotted two late penalties to boost morale ahead of two home Rugby Championship matches against arch rivals New Zealand next month.