The 18-year-old wonderkid was selected for the Under-21s, whom he is yet to make an appearance for, before being swiftly promoted to Gareth Southgate's ranks for March's double-header with the Selecao and Belgium.
The uncapped quartet also comprises Ezri Konsa, Jarrad Branthwaite and Anthony Gordon, who will likely take their spots on the bench alongside Mainoo, while another four players are yet to take part in team training since arriving at St George's Park.
Indeed, Bukayo Saka, Cole Palmer and Jordan Henderson were all restricted to gym work on Wednesday, as was Harry Kane, who suffered an ankle scare in Bayern Munich's most recent Bundesliga match.
As a result, the Three Lions captain may be wrapped in cotton wool this week, allowing Aston Villa's Ollie Watkins and Brentford's Ivan Toney the chance to fight it out for a starting role, a battle which the former should win.
With Saka and Palmer also being protected, Jarrod Bowen is a candidate to occupy the right-wing position, while Marcus Rashford is in line to start on the left due to Jack Grealish's absence through injury.
A star-studded midfield trio of Phil Foden, Jude Bellingham and Declan Rice could very well grace the Wembley turf from the first whistle too, while Kyle Walker, John Stones, Harry Maguire and Jordan Pickford are mainstays at the back.
Ben Chilwell has been included in the squad despite a recent knee concern, but given his history of physical woes, Joe Gomez - recalled for the first time since 2020 - has a case to start at left-back, where he has done an exemplary job for Liverpool in recent months.
England possible starting lineup:
Pickford; Walker, Stones, Maguire, Gomez; Foden, Rice, Bellingham; Bowen, Watkins, Rashford