After a summer of speculation and change behind the scenes, Erik ten Hag - retained after winning the FA Cup against Manchester City - wanted to start the season with a bang at a packed Old Trafford.
United showed promise in patches but looked set to be frustrated by Marco Silva's Fulham, only for Zirkzee to turn in a cross from fellow substitute Alejandro Garnacho in a late 1-0 win.
The Netherlands international did not play a minute of United's pre-season friendlies, having arrived late following Euro 2024 and his 61st-minute introduction proved inspired.
Zirkzee, signed from Bologna, was brought on as part of a double change alongside Garnacho, whose cross he prodded home to secure an opening-night triumph in the 87th minute.
It was some introduction on a night that began with the Netherlands international and United's three other summer signings being welcomed by the Old Trafford faithful.
There was a feel-good factor around the ground, but Fulham looked undaunted as Adama Traore surged down the right and saw a cutback cut out by Red Devils debutant Noussair Mazraoui.
There was a huge early roar as Lisandro Martinez barged the rapid winger off the ball, before United's own fleet-footed wide man got bums off seats.
Amad Diallo's penalty appeal at the end of that run fell on deaf ears and Fulham broke, with Kenny Tete's 25-yard curler needing to be turned over by Andre Onana.
"We want Glazers out" chanted fans as co-owner Avram Glazer watched from the directors' box with United looking smart in patches without creating clear-cut chances.
Their first came in the 29th minute as an impressive press led Bernd Leno to cough up possession, only for the goalkeeper to deny Bruno Fernandes after Casemiro had cut out his pass.
The Fulham shot-stopper spread himself again to deny the United captain soon after as quick build-up play ended with Casemiro superbly slipped in the Portuguese to get away a shot.
The Brazil international headed narrowly wide and then volleyed far further off target as the first half of the season ended scoreless.
Fulham unsteadied the hosts when the second half got under way and had a couple of half-chances from corners.
But United quickly shook off that raggedness, with Mason Mount denied after a Marcus Rashford burst before Kobbie Mainoo fired inches wide.
Fulham were having to defend well but were still creating chances, with Onana stopping a blocked Rodrigo Muniz overhead kick looping in before some stupendous Harry Maguire defending.
The visitors had a two-on-one opportunity, but the centre-back held his ground and cut out former United midfielder Andreas Pereira's ball in the 66th minute.
Fulham again outnumbered the Red Devils on the break in the 74th minute, but once more they failed to capitalise. This time Martinez made the key intervention, cutting out Pereira's ball to the far post at the end of a sweeping move.
A Fernandes shot was plucked out of the air by Leno as the clock wound down towards what appeared set to be a goalless draw.
But for the issues United have under Ten Hag their spirit can rarely be questioned and Zirkzee bought straight into it.
The new arrival played wide and ran into the box three minutes from time, stretching to direct Garnacho's cross from the right past Leno in front of the Stretford End.
Provider Garnacho should have added to that goal in stoppage time after Rashford's selfless pass after a Calvin Bassey error but the Argentina winger somehow missed an open goal.
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