Teenage wing Louis Rees-Zammit and Saracens centre Nick Tompkins are among five uncapped players in Wayne Pivac's first Six Nations Wales 38-man squad.
Rees-Zammit, 18, has starred for Gloucester while Tompkins is eligible through a Welsh grandmother.
The other uncapped players in the reigning Six Nations champions' squad are prop WillGriff John, lock Will Rowlands and back Johnny McNicholl.
There are recalls for British and Irish Lions Taulupe Faletau and Rhys Webb.
Number eight Faletau has been ravaged by injury since last playing for Wales in March 2018, missing last year's World Cup with a broken collarbone.
Webb had been ineligible for Wales since the Welsh Rugby Union (WRU) introduced a selection policy in October 2017 that meant players would not be picked if they had won fewer than 60 caps and opted to move away from Wales.
The WRU confirmed earlier this month Webb will be eligible for immediate selection after announcing he will return from Toulon to re-join Ospreys next season.
The 31-year-old's selection alongside fellow scrum-halves Gareth Davies and Tomos Williams means Ospreys' Aled Davies misses out.
Ospreys loose-head prop Nicky Smith and second-row Bradley Davies are among the other notable absentees.
Meanwhile, there are also recalls for Gloucester fly-half Owen Williams, Leicester back Jonah Holmes and Cardiff Blues forward Seb Davies.
Rees-Zammit born in Cardiff, signed his first senior contract with Gloucester and has expressed his desire to play for Wales.
As the contract is his first senior deal, Rees-Zammit remains eligible for selection for Wales despite playing in England.
The teenager has been in fine form for Gloucester this season having scored nine tries in 12 senior games, including an eye-catching hat-trick against Northampton.
Wasps lock Rowlands is eligible through his Wales father, while Sidcup-born Tompkins qualifies through a Welsh grandmother born in Wrexham.
The 24-year-old was part of the England Under-20s side that won the Junior World Championships in 2014 and has also played for England Saxons.
"It is a huge honour to have been asked to join the Welsh squad," said Tompkins.
"My grandmother was born in Wrexham, and I have cousins who are regulars at the Principality stadium in Cardiff.
"It's true that I played for England through the age-groups, but I have always felt part Welsh and part English.
"I am massively excited by the prospect of wearing the red jersey and playing for the most passionate supporters in world rugby."
Wales have mounting injury issues at centre, with Scarlet Jonathan Davies and Cardiff Blues' Willis Halaholo ruled out of the tournament with serious knee injuries and Owen Watkin missing at least the opening match.
Watkin has been named in the squad, while other options for the 13 jersey include the possibility of wings George North, Josh Adams or Owen Lane or fly-half Williams being asked to play out of position.
New Zealand born McNicholl, who qualifies through residency, is selected for a second Wales squad after scoring against Barbarians in the uncapped international victory in November 2019.
Pivac has been hampered by other injury problems.
Ospreys outside-half Gareth Anscombe and Exeter prop Tomas Francis will miss the tournament, while Scarlets-bound Saracens back Liam Williams has not played since suffering an ankle injury at the World Cup, but is included in the squad.
Cardiff Blues back Hallam Amos (ankle) and Scarlets flanker James Davies (back) both miss out on selection due to their respective injuries.
Wales open their Six Nations campaign against Italy on Saturday, 1 February before travelling to face Ireland seven days later. The squad meet up on Monday, 20 January.
Saracens prop Rhys Carre faces a disciplinary panel on Wales' squad announcement day after being sent off for an alleged high tackle against Ospreys in the European Champions Cup last weekend.
"A lot of time and effort has gone into selecting the squad, all of the coaches have been out and about, seeing players in training, speaking with them and we are pretty excited with the group we have got," said Pivac, who watched Tompkins as his Saracens side beat Ospreys in Swansea last Saturday.
"We do have a couple of injuries but we flip that into seeing it as an opportunity for some new players to impress, with not only the Six Nations in mind but also longer term and 2023.
"The Six Nations is hugely exciting for me, it is something I grew up watching from afar and it has such history attached to it, I'm really looking forward to the campaign."
Wales squad for 2020 Six Nations
Forwards: Rhys Carre (Saracens), Rob Evans (Scarlets), Wyn Jones (Scarlets), Elliot Dee (Dragons), Ryan Elias (Scarlets), Ken Owens (Scarlets), Leon Brown (Dragons), WillGriff John (Sale), Dillon Lewis (Blues), Jake Ball (Scarlets), Adam Beard (Ospreys), Seb Davies (Blues), Alun Wyn Jones (capt; Ospreys), Will Rowlands (Wasps), Cory Hill (Dragons), Aaron Shingler (Scarlets), Aaron Wainwright (Dragons), Taulupe Faletau (Bath), Ross Moriarty (Dragons), Josh Navidi (Blues), Justin Tipuric (Ospreys).
Backs: Gareth Davies (Scarlets), Rhys Webb (Toulon), Tomos Williams (Blues), Dan Biggar (Northampton), Owen Williams (Gloucester), Jarrod Evans (Blues), Hadleigh Parkes (Scarlets), Nick Tompkins (Saracens), Owen Watkin (Ospreys), George North (Ospreys), Josh Adams (Blues), Owen Lane (Blues), Johnny McNicholl (Scarlets), Louis Rees-Zammit (Gloucester), Jonah Holmes (Leicester Tigers), Leigh Halfpenny (Scarlets), Liam Williams (Saracens).