The Red Devils can move six points clear at the top of the Premier League table with a win against their local rivals at the Etihad Stadium.
However, victory for City would see the Blues go above United on goal difference at the top of the pile with just two games to play.
"This derby is a final for us. If we beat City, United will be Premier League champions again. It's as simple as that — we are 90 minutes from winning the title," De Gea told The Sun.
"I never believed this derby would be so decisive.
"I have lived through derbies in Madrid and this one is more important, especially with a title resting on it."
The Spaniard moved to Old Trafford from Atletico Madrid in the summer.