The Exiles had won just one of their last six matches against Sarries but led 22-8 at the break thanks to tries from Matt Parr, Alex Lewington and George Skivington.
Saracens had led briefly through Marcelo Bosch's try in the 13th minute but - despite London Irish twice being reduced temporarily to 14 men - the league leaders failed to build any momentum.
Schalk Brits' try five minutes before the end gave them hope but Charlie Hodgson failed with the conversion attempt as Irish ran out 22-13 winners to give Northampton Saints the chance to take over at the top later in the day.
Shane Geraghty put the kick-off straight into touch but Saracens were penalised at the resulting scrum and, from the halfway line, James O'Connor put Irish ahead after three minutes.
After nine minutes Fergus Mulchrone was sent to the sin-bin for the Exiles after they were penalised at the breakdown for a fifth time in the opening minutes.
And five minutes later Saracens made their pressure pay. A quickly taken penalty five metres out was held up on the line but Hodgson spread the ball to Bosch on the overlap who went over for his first try for Saracens.
With Mulchrone back on the field the visitors grew into the game and they went ahead on 21 minutes through Parr's first Premiership try, the prop collecting Nic Rouse's off-load after clever play by Tomas O'Leary.
Blair Cowan became the second Exile to be sent to the bin but a Hodgson penalty was the hosts' only reward with the flanker off the pitch.
But the visitors shocked the home side with two tries in three first-half minutes as the match approached half-time.
First Hodgson's kick was charged down and O'Leary passed to winger Lewington, who crossed in the corner before Exiles captain Skivington went over on his return after scrappy play in midfield saw the ball kicked on several times.
O'Connor converted the latter having also added the extras to Parr's score to send the Exiles in 22-8 up at the break.
England centre Joel Tomkins made his return after three months out with a knee injury on 52 minutes.
With seven minutes remaining Brits broke through a gap in midfield to take play within 10 metres of the London Irish line.
The ball was recycled and spread wide before the visitors were penalised for a high tackle.
Saracens went for the scrum and finally burrowed over through Brits, though Hodgson's missed conversion ensured Sarries lost a regular season match for the first time at Allianz Park.