Wing George North will feature at centre and Ellis Jenkins will captain Wales for the first time in Saturday's Test match against South Africa.
It will be 73 times-capped North's fourth Test start in midfield, where he is partnered by Ospreys' Owen Watkin.
Ospreys-bound North's previous centre outings for Wales were against France four years ago and against Australia in 2014 and 2015.
Head coach Warren Gatland, who has rested almost all of the Wales players that were on British and Irish Lions duty in New Zealand last summer, hands a first cap to Cardiff Blues scrum-half Tomos Williams.
Williams, 23, will be joined at half-back by his Blues colleague Gareth Anscombe for the game in Washington, DC.
Flanker Jenkins, meanwhile, led the Blues to European Challenge Cup final success earlier this month, and was named Wales' tour co-captain with Dragons lock Cory Hill.
There are also opportunities for the likes of Scarlets wing Tom Prydie and Blues prop Dillon Lewis as Wales prepare to face a Springboks team containing seven uncapped players. It will be Prydie's first Wales appearance since 2013.
Uncapped Dragons forward Aaron Wainwright is among the replacements alongside a number of Scarlets players, including prop Wyn Jones, hooker Ryan Elias, scrum-half Aled Davies and centre Hadleigh Parkes.
Fly-half Rhys Patchell, meanwhile, is due to be on the bench but he faces a fitness test ahead of the game, with Scarlets number nine Gareth Davies stepping in if Patchell fails it.
Gatland said: "Saturday is a huge opportunity for this squad and for players individually. Everything we are doing is geared for the World Cup in 15 months' time, and the next three matches are a hugely important part of our development.
"This weekend is an opportunity for players to build on their Test rugby experience and lay a marker down for the jersey and for the position going forward.
"I think there are exciting selections across the team and I'm looking forward to Saturday to see what we are able to do against the Springboks."
After the South Africa game, Wales head to South America for Tests against Argentina on June 9 and 16.
Wales team to play South Africa on Saturday: H Amos (Dragons); T Prydie (Scarlets), G North (Ospreys), O Watkin (Ospreys), S Evans (Scarlets); G Anscombe (Cardiff Blues), T Williams (Cardiff Blues); N Smith (Ospreys), E Dee (Dragons), D Lewis (Cardiff Blues), B Davies (Ospreys), C Hill (Dragons), S Davies (Cardiff Blues), E Jenkins (Cardiff Blues, capt), R Moriarty (Dragons).
Replacements: E Elias (Scarlets), W Jones (Scarlets), R Jones (Ospreys), A Beard (Ospreys), A Wainwright (Dragons), A Davies (Scarlets), R Patchell (Scarlets), G Davies (Scarlets), H Parkes (Scarlets).