Gloucester back Owen Williams will make his first Test match start when Wales face Australia in Cardiff on Saturday.
Williams, who was capped as a replacement during Wales' tour match against Tonga earlier this year, lines up at inside centre, the Welsh Rugby Union has announced.
There are also opportunities for Scarlets wing Steff Evans and Cardiff Blues flanker Josh Navidi, with Navidi packing down alongside back-row colleagues Aaron Shingler and Taulupe Faletau.
British and Irish Lions Test full-back Liam Williams, meanwhile, is on the wing, as Leigh Halfpenny retains the number 15 shirt, and there are three uncapped players among the replacements in Dragons prop Leon Brown, plus Ospreys pair Owen Watkin and Sam Cross.
Cross, who has played less than a handful of senior 15-a-side games, featured in the Great Britain sevens squad that won an Olympic silver medal at Rio 2016.
Wales, beaten 12 times in a row by Australia, are without key names such as Sam Warburton, Justin Tipuric, Samson Lee, Rhys Webb and George North.
Williams' selection alongside fly-half Dan Biggar represents a shift of tactical emphasis by Wales head coach Warren Gatland as he fields two midfield playmakers.
It is an approach that Gatland operated with considerable success on the Lions' New Zealand tour earlier this year when Johnny Sexton and Owen Farrell filled those roles, while England head coach Eddie Jones also employs such a system with great effect, pairing together Farrell and George Ford.
Elsewhere behind the scrum, Gareth Davies will be Biggar's half-back partner as Webb continues his recovery from a knee injury, and Scarlets try machine Evans is handed an opportunity to show his blistering domestic form on the international stage.
The back-row, though, is all-change from Wales' final game of last season's Six Nations campaign, with injured Warburton and Tipuric unavailable and Ross Moriarty only having started his comeback for Gloucester last weekend following a lengthy injury absence.
Lock Alun Wyn Jones captains the side and wins his 111th cap, with Jones among seven Lions on duty in New Zealand this summer that feature in the starting XV.
Gatland said: "We are really looking forward to Saturday and getting the Under Armour Series under way.
"I am delighted for Steff Evans, Owen Williams and Josh Navidi that they get their first start at home. The atmosphere will be fantastic, and it's a great opportunity for them.
"It's going to be a tough first-up game. We know that, and we need to be up and running.
"We have a squad that is packed with talent and is on form, and we are excited to see what they can do."
Gatland, who reached the 10th anniversary of his appointment as Wales boss on Thursday, masterminded a narrow victory over Australia in 2008.
But it has been a consistent tale of disappointment for Wales in the fixture since then, even through a number of losses were by low single figure margins.
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