The Belgian has not started a first-team game since February 11 but he boosted his chances of a recall with a standout display for the second string in a match that saw James Wilson also hit the target.
Almost 17,000 at Old Trafford watched a victory that moves Warren Joyce’s side to within a point of the league crown, their final game of the campaign a return fixture against City that is still to be arranged.
Januzaj, who started on the left of a front three, teed up Wilson with just five minutes on the clock when he spotted the forward’s run and delivered a 40-yard ball that was neatly tucked away.
City had bossed possession with making it count, though Kean Bryan tested Joel Pereira from 25 yards on the half-hour mark, the United’s goalkeeper down swiftly enough to push his shot around the post.
Instead, United doubled their lead soon after the restart, Joe Rothwell latching onto a loose ball and sliding into the path of Januzaj.
The 20-year-old cut inside, rode two tackles and found the bottom corner, leaving to a standing ovation when he was substituted in the 73rd minute.
United continue to play on the break and Wilson raced away to tee up Ashley Fletcher for a third, before substitute Matthew Willock curled a fourth in off the post.
The youngsters’ performance caught the eye of several first-teamers, including Ashley Young, who tweeted: “Top night for our U21s, great 4-0 result against Man City at Old Trafford. Well done!”
Phil Jones posted: “Brilliant performance from @ManUtd U21s tonight. Great turnout under the lights at Old Trafford. Well done boys!”