Manchester United endured a disappointing day in North London as Arsenal inflicted the club’s first Premier League defeat since October.
Two second-half goals in quick succession proved decisive for the Gunners as Granit Xhaka and former United striker Danny Welbeck got on the scoresheet.
Jose Mourinho made eight changes to his United line-up that beat Celta Vigo on Thursday with Juan Mata making his first start since returning from groin surgery and young defender Axel Tuanzebe given his Premier League debut.
With the unbeaten league run standing at 25 games ahead of kick-off, the Reds were looking to close the gap on the top four to just one point after Liverpool dropped two points at home to Southampton earlier in the day.
It was a bright start from both sides and United had a first sight of goal inside two minutes when Mata’s cross from the right found Wayne Rooney, only for the captain to head over.
With both sides needing a win to keep pace in the race for the top four, it soon became an end-to-end encounter with Aaron Ramsey first going close for the hosts after a clever through ball from Alexis Sanchez allowed the Welshman to force De Gea into an outstanding low save to his right.
Welbeck led the line for the Gunners and just before the half-hour mark he controlled the ball with his back to goal inside the six-yard box, turned to shoot but it was smartly blocked by a lunging Phil Jones.
That chance ignited Arsenal and they went close again moments later when Alex Oxlade-Chamberlain picked up the ball 25 yards out and rifled an effort, which took a deflection, straight at De Gea who palmed it to safety.
With Arsenal turning the screw, a counterattack almost led to United forging ahead as a poor backpass from Rob Holding put Rooney through on goal but his effort was smothered by Petr Cech.
Possession: Arsenal 49% United 51%
Shots at goal: Arsenal 5 United 4
Shots on target: Arsenal 2 United 2
Corners: Arsenal 5 United 5
The second half started as evenly as the first with both sides enjoying plenty of possession in the opening few minutes but a frantic three-minute period saw United fall 2-0 behind.
On 54 minutes, Xhaka opened the scoring from 25 yards as his effort took a fortuitous deflection off the back of Ander Herrera, allowing it to loop over De Gea at full stretch.
Before United could get themselves back into the game, a deep right-wing cross from Oxlade-Chamberlain picked out Welbeck between two defenders and the former Reds striker headed home.
Mourinho responded by introducing the pace of Jesse Lingard and Marcus Rashford, but the game quietened down thereafter with Arsenal looking to keep possession. With 10 minutes to go, Rooney sent a curling effort towards Cech’s top corner but it was just off target.
With five minutes remaining, young United midfielder Scott McTominay was brought on to make his first-team debut and from a Smalling knockdown, he fired a low effort at goal that was well collected by Cech.
Arsenal held firm for the victory to leave the Reds very much focused on the Europa League and Thursday’s semi-final second leg against Celta Vigo at Old Trafford.
Possession: Arsenal 50% United 50%
Shots at goal: Arsenal 9 United 9
Shots on target: Arsenal 4 United 3
Corners: Arsenal 5 United 8
Arsenal: Cech, Holding, Koscielny, Monreal, Oxlade-Chamberlain (Bellerin 84), Ramsey, Xhaka (Coquelin 76), Gibbs, Ozil, Sanchez, Welbeck (Giroud 84).
Subs not used: Ospina, Gabriel, Iwobi, Walcott.
United: De Gea; Tuanzebe, Smalling, Jones, Darmian; Carrick, Herrera (Rashford 63); Rooney (c), Mata (McTominay 85), Mkhitaryan (Lingard 61), Martial.
Subs not used: Romero, Bailly, Blind, Pogba.