The versatile defender will become the Citizens' third-youngest player in their history and the youngest player to be given his first-team bow under manager Pep Guardiola.
Braithwaite, who has started all four games for City's Under-18s this season, is one of nine changes made to Guardiola's side following Sunday's pulsating 2-2 Premier League draw with Arsenal.
Captain Kyle Walker and Jeremy Doku are the only two players in City's lineup who started against Arsenal, with the former set to join Braithwaite, John Stones and Rico Lewis in a four-man defence, protecting goalkeeper Stefan Ortega.
Academy starlet Nico O'Reilly, who made his first-team debut against Manchester United in the Community Shield last month, is handed another start in midfield tonight alongside Matheus Nunes and James McAtee, the latter - along with O'Reilly - is starting as a senior player at the Etihad for the first time.
Phil Foden is handed his first start of 2024-25, and last season's PFA Player of the Year is set to link up with Doku and Jack Grealish in attack.
As for Watford, Tom Cleverley has also made a total of nine changes to the side that lost 4-1 away against Norwich City in the Championship last weekend.
Experienced defender Angelo Ogbonna will make his debut having joined from West Ham United on a free transfer this summer. The 36-year-old will line up alongside James Morris and Ryan Porteous in a back three, with Festy Ebosele and Yasser Larouci set to operate as wing-backs.
Imran Louza, Tom Ince and Kwadwo Baah have also been brought into the side, with Ken Sema retaining his starting spot, and they will all provide support for central striker Vakoun Bayo.
Manchester City starting lineup: Ortega; Walker, Stones, Braithwaite, Lewis; O'Reilly, Nunes, McAtee; Doku, Foden, Grealish
Subs: Ederson, Dias, Kovacic, Gundogan, Bernardo, Gvardiol, Akanji, Savinho, Wright
Watford starting lineup: Bond; Porteous, Ogbonna, Morris; Ebosele, Louza, Sema, Larouci; Ince, Bayo, Baah
Subs: Marriott, Pollock, Chakvetadze, Vata, Dwomoh, Tikvic, Doumbia, Dele-Bashiru, Adu-Poku