Bath wing Watson has not featured for Eddie Jones' team since the World Cup because of a calf problem, but he replaces Jonathan Joseph, who drops out of the matchday 23 altogether.
Sale Sharks star Wilson will also feature for the first time since the World Cup after recovering from a knee injury and he will join Courtney Lawes and Tom Curry in the back-row after Sam Underhill was ruled out of Saturday's match with an unspecified injury.
It was already confirmed that prop Mako Vunipola would not be included in the squad, as he was left out due to precautions regarding the coronavirus after he travelled through Hong Kong on his return from Tonga last weekend.
England will be looking to maintain their hopes of winning the Six Nations after responding from their round one defeat to France with victories over Scotland and Ireland.
Meanwhile, defending Grand Slam champions Wales have lost two of their three games during this year's tournament, although Jones certainly won't be underestimating Wayne Pivac's team.
"Wales are a very tough, well-coached side and they've been building on their attack since Wayne Pivac has taken over," the 60-year-old said.
"It's always a tough game against Wales and we know they will bring that toughness to all the contest areas."
It has also been confirmed that England's final Six Nations match with Italy, which was scheduled to take place on March 14, has been postponed over concerns regarding the coronavirus.
The game will now be played at a later date after both the Six Nations and the Italian rugby federation decided against playing the match behind closed doors.
England: 15 Elliot Daly, 14 Anthony Watson, 13 Manu Tuilagi, 12 Owen Farrell (c), 11 Jonny May, 10 George Ford, 9 Ben Youngs; 1 Joe Marler, 2 Jamie George, 3 Kyle Sinckler, 4 Maro Itoje, 5 George Kruis, 6 Courtney Lawes, 7 Mark Wilson, 8 Tom Curry.
Replacements: 16 Luke Cowan-Dickie, 17 Ellis Genge, 18 Will Stuart, 19 Joe Launchbury, 20 Charlie Ewels, 21 Ben Earl, 22 Willi Heinz, 23 Henry Slade.