The defensive duo arrived at Old Trafford just three days ago in a £60million double deal from Bayern Munich but Erik ten Hag has opted to leave De Ligt among his substitutes with Harry Maguire and Lisandro Martinez selected instead.
The Netherlands centre back has taken part in only a handful of sessions alongside his team-mates but has made United's matchday squad as expected.
Mazraoui has been drafted in at left back with Luke Shaw ruled out through injury.
Speaking at his pre-match press conference, Ten Hag revealed he had no concerns about giving both players their debuts so soon after joining.
Matthijs de Ligt has been named on Man United's bench for their Premier League opener
'Issues are there,' Ten Hag said. 'But it's not about the players who are not available. Same as last season it's about the players who are available.
'We have a good group, we can make a strong selection and we can put out a strong team and we will do. They will be in the squad.'
De Ligt and Mazraoui became United's third and fourth signings of the summer, following in the footsteps of Joshua Zirkzee and Leny Yoro, and previously worked under Ten Hag during their respective spells at Ajax.
Yoro will be absent for several weeks due to a foot issue while Rasmus Hojlund is also missing as United begin the new top-flight campaign at Old Trafford.
Jadon Sancho has missed out on the squad, however, with his future uncertain.
There are starts for Mason Mount and Bruno Fernandes while Amad Diallo will continue down the right wing after catching the eye in pre-season.
Alejandro Garnacho, on target in the Community Shield, is on the bench alongside Zirkzee, who did not make his maiden United appearance at Wembley.
Scott McTominay, linked with a move this month, is also among the substitutes.