With Euro 2024 qualification already secured, Gareth Southgate has handed Aston Villa striker Watkins a rare start as he leads the line in Skopje.
Neither Jarrod Bowen nor Kieran Trippier have travelled for the match. West Ham forward Bowen suffered an injury in training and will not be risked, while Newcastle's Trippier left the squad to tend to "a personal matter".
It leaves Gareth Southgate with just 21 available players for England's final match of 2023.
Jack Grealish starts after being rested in Friday's 2-0 win over Malta at Wembley, while Declan Rice also features from the off in an exciting midfield alongside Trent Alexander-Arnold and Phil Foden.
England were already without a nominal left-back in the squad due to long-term injuries for Ben Chilwell and Luke Shaw, and the absence of Trippier means Southgate has given Rico Lewis a senior debut.
The England boss deployed right-footed centre-back Fikayo Tomori at left-back in the win against Malta on Friday, but the AC Milan player struggled and is not trusted there again.
Southgate said in his pre-match press conference: “We’ve got a couple of options [at left-back]. We can find a couple of different solutions to the issue.
"We’ve adapted to a lot of situations over the last few years, and we’re comfortable doing that again tomorrow. Fik did it the other day, Rico Lewis, Marc Guehi can play there.”
England XI (4-3-3): Pickford; Walker, Maguire, Guehi, Lewis; Rice, Alexander-Arnold, Foden; Saka, Watkins, Grealish
Subs: Johnstone, Ramsdale, Tomori, Henderson, Phillips, Gallagher, Konsa, Rashford, Palmer, Kane
Date and time: 7:45pm GMT on Monday November 20, 2023
Venue: Tose Proeski National Arena in Skopje