Warren Gatland's RBS Six Nations champions fell by 37 points to 21, a 16-point margin that flattered the home side. With 20 minutes remaining it was anyone's match, smart defence from Wales keeping South Africa at bay.
But in the end victory was too much of an ask and a late try by replacement prop du Plessis put a gloss on the scoreline for the home fans. Shane Williams produced a moment of magic but it was not enough to prevent Wales recording their second straight defeat to South Africa in the 2008 summer tour.
Wing wizard Williams scored his 43rd Test try and looked set to hand the dragons their first ever win on the Springboks' home soil. Williams's sensational try put Wales 15-14 ahead on 31 minutes in a much-improved performance from Gatland's men.
But the world champions proved their worth after the interval and killed off Wales's hopes with second half tries through star centre Jean de Villiers - who scored a brace - and prop Bismarck du Plessis.
Gatland's troops arrived at the scene of their heaviest ever defeat - 96-13 a decade ago - having been easily defeated by the Springboks in Bloemfontein last weekend.
Prop Gethin Jenkins was the sole survivor from last week's front-row after a display that impressed British Lions Coach Ian McGeechan and he needed to step up again against 18-stone stone Zimbabwean monster Tendai 'The Beast' Mtawarira.
South Africa Coach Peter de Villiers beefed up his pack with World Cup winner Victor Matfield to apply more pressure on the Welsh line-out. But Wales got off to a flying start on five minutes thanks to Stephen Jones's fifth minute penalty.
The hosts looked to test Hook's last line of defence early on but the Ospreys star produced a huge tackle to rock Matfield on seven minutes and deny the veteran the first try.
But the retentless pressure from the Springboks eventually told on 11 minutes when centre Jean De Villiers, who grabbed a try in last week's hammering, crashed over again from close range.
Butch James enjoyed a 100% kicking record with nine from nine in Bloemfontein and maintained his rich vein of form with the conversion.
Wales were on the back foot and de Villiers's men extended their lead when scrum half Ricky Januarie finished off a free-flowing South African attack. Matfield released rampaging flanker Juan Smith who broke the Wales defence and his deft offload found the supporting Januarie who touched down.
But the dragons hit back instantly through Gareth Cooper's opportunist try. Skipper Ryan Jones won the line-out and Gloucester scrum half Cooper broke through on the blindside before side-stepping the last South African defender to score. Jones converted to reduce the deficit to just four points as Wales showed real competitiveness.
And defence guru Shaun Edwards would have been pleased with the much-improved defensive performance and tiger-like tackling. Then Shane Williams produced another moment of brilliance to put Wales into a unexpected lead.
Wales's record try-scorer Williams pounced on a loose ball on the halfway line and scored one of his finest tries and his 43rd of his international career. Williams bobbed and waived like fellow Welshman Ryan Giggs in the 1999 FA Cup semi-final to touch down in sensational style in the left corner.
But Wales conceded a penalty on the stroke of half time and James handed the Springboks a 17-15 interval lead. James grabbed his second penalty on 49 minutes to edge the Springboks further ahead but Jones reacted with a similar riposte moments later.
De Villiers looked on with worry and sent on several replacements to inject some momentum into the South Africans. And it worked a treat as veteran Percy Montgomery set up De Villiers for his second try on 65 minutes.
Wales kept their pride intact but du Plessis had the final say when he drove over in the final minute to cement a 2-0 series win for South Africa.
Tries: De Villiers (2), Januarie, du Plessis
Cons: James (4)
Pens: James (3)
Tries: Cooper, S Williams
Cons: S Jones
Pens: S Jones (3)
South Africa: C Jantjes; T Chavhanga (P Montgomery 63), A Jacobs (F Steyn 58), J De Villiers, B Habana; B James, R Januarie (B Conradie 71); T Mtawarira (G Steenkamp 58), J Smit (capt) (B Du Plessis 58), BJ Botha, B Botha (A Bekker 63), V Matfield, L Watson, P Spies (R Kankowski 58), J Smith
Wales: J Hook; M Jones (T James 77), T Shanklin (A Bishop 68), J Roberts, S Williams; S Jones, G Cooper (W Fury 73); G Jenkins, R Hibbard (T Thomas 71), R Thomas (Duncan Jones 70), I Gough, AW Jones, R Jones (capt) (I Evans 68), G Delve (Dafydd Jones 21), J Thomas