Leicester's Watson replaces the injured Ollie Hassell-Collins on the wing in the only change to the starting XV that beat Italy in round two.
Vice-captain Courtney Lawes is set for his first England appearance since July having been named on the bench.
Ben Curry is also a replacement after being called into the squad when brother Tom was injured.
With the experienced Jonny May and Jack Nowell left out of new head coach Steve Borthwick's original Six Nations squad, Hassell-Collins led the way for a new generation to shine.
But instead of giving Harlequins' Cadan Murley, 23, a chance, Borthwick has favoured the perhaps more reliable 28-year-old Watson as Max Malins continues on the other wing after impressing in the opening rounds.
Former captain Lawes, 34, is back after a string of injuries including concussion as well as neck, glute and calf issues that meant he missed the narrow opening defeat by Scotland and victory against Italy.
With Tom Curry out for the rest of the tournament because of a hamstring injury, Borthwick retains a back row of Lewis Ludlam, Jack Willis and Alex Dombrandt.
In the backline, captain Owen Farrell once again starts at fly-half as Marcus Smith is the replacement number ten.
England - who have not won in Cardiff since 2017 - are third in the Six Nations table, while winless Wales are sixth.