Belgium beat England twice at the 2018 FIFA World Cup and was ahead after 15 minutes at Wembley through Romelu Lukaku's penalty, awarded when the Inter forward was brought down by Eric Dier.
It was the first goal Gareth Southgate's side had conceded in a year but it drew level before the interval, Thomas Meunier conceding a soft spot-kick from which Marcus Rashford scored.
Having spent much of the first half on the back foot, England looked reinvigorated for the second period and got its reward when Mount's shot looped off Toby Alderweireld and beyond Simon Mignolet's reach, as the world's top-ranked footballing nation was beaten for the first time since November 2018.
Yannick Carrasco lashed home what appeared to be an 11th-minute opener, but Timothy Castagne was adjudged offside in a position that was obstructing the view of goalkeeper Jordan Pickford.
The host was looking to keep a seventh consecutive clean sheet, which would have constituted an England record, but those hopes were scuppered when Dier felled Lukaku in the box and the forward picked himself up to convert the spot-kick.
Lukaku produced a dominant display that summed up Belgium's early control of the contest, with England struggling to get a foot on the ball or lay a finger on the former Manchester United star.
But Southgate's side were handed a route back into the match when Jordan Henderson went down under minimal contact from Meunier and Rashford confidently fired home from 12 yards.
Belgium saw a 12-game winning run halted with Thursday's 1-1 draw versus Ivory Coast, while England were seeking a 20th win from 21 home matches, ensuring neither side was likely to willingly budge an inch in the second half.
It was England who started the period with a greater purpose but it took until the 64th minute for the next goal to arrive, Mount's shot ricocheting off Alderweireld and over Mignolet.
Roberto Martinez's men tried to force the issue inside the final 20 minutes, with Carrasco stabbing narrowly wide and Lukaku thwarted soon after, while substitute Harry Kane missed an excellent headed chance at the other end.