The Exiles were rocking shortly before the interval as Harlequins raced into a 20-3 lead with tries from Ugo Monye and Tom Guest.
But Armitage landed a vital counter-punch shortly before the interval with a breakaway try and London Irish then dominated the second half to rack up 25 unanswered points.
Armitage touched down again before Exiles full-back Peter Hewat intercepted a pass from Chris Robshaw and raced 75 metres. Hewat finished with a personal haul of 18 points as he kicked the Exiles two scores clear.
Harlequins' England scrum-half Danny Care set up a frantic last 90 seconds with a late converted try - but London Irish held out and returned to winning ways after two straight defeats.
Following complaints last week from Harlequins boss Dean Richards that Gloucester's Dean Ryan had influenced the referee at half-time it was somewhat ironic that the referee at The Stoop today was a certain Dean Richards. And there were a few smirks when the RFU's whistle-blower then penalised Quins inside the opening minute, allowing Hewat to kick London Irish ahead.
But there was little else for the Exiles to smile about for most of the first half as Harlequins defied the current Premiership trend to play some adventurous rugby and were substantially rewarded with a 20-8 lead at the interval.
The usually well-oiled London Irish lineout malfunctioned while Quins were sparked by the lively David Strettle, whose powerful 35-metre run created the opening try.
Strettle, renowned for his quick footwork, showed watching England coach Brian Smith he has a tough side as he broke four tacklers to race within touching distance of the London Irish line. Strettle was finally hauled down but the Exiles were broken and a lofted pass from Chris Malone teed up Monye to score in the corner. With Malone slotting the conversion and two penalties, Quins quickly led 13-3.
London Irish had their moments with Topsy Ojo and Peter Richards helping the Exiles move to within five metres of the try-line but Quins defended stoutly and were much more efficient in attack.
Guest blazed over half-way, Malone and the sparky Danny Care kept the ball alive and Quins worked a comfortable overlap where Guest was on hand to finish off the move.
The ball did eventually run for the Exiles shortly before the interval when Delon Armitage won the race to touch down in the corner after Hewat had twice hacked the it forward. And Irish carried that momentum into an extraordinary second half. The Exiles bossed possession and were camped in the Harlequins half for nearly 20 minutes before making the dominance count.
Hewat and fly-half Eoghan Hickey both missed penalty attempts and when Sailosi Tagicakibau had a sniff of an opening down the left wing, play was called back for a forward pass.
Hewat eventually slotted a simple penalty and Irish quickly hit Quins again, moving the ball out wide quickly for Armitage to score his second of the afternoon.
The try was awarded without question although Care was insistent that Armitage's dive had taken him onto or over the dead-ball line. Quins needed to conjure up a response but Hewat was alive to Robshaw's pass and raced 75 metres to score an interception try under the posts. Hewat converted his own try and then pushed Irish two scores clear with a vital penalty which crept over after rattling off the left post.
Care set up a frantic finish when he scored from close range following another Strettle break with two minutes remaining but the Exiles held out for the win.
Harlequins 27 (20) Tries: Monye, Guest, Care Cons: Malone (2), Luveniyali Pens: Malone (2)
London Irish 28 (8) Tries: D Armitage (2), Hewat Cons: Hewat (2) Pens: Hewat (3)
Harlequins: Brown, Strettle, Tiesi, Turner-Hall, Monye, Malone, Care, Jones, Botha, Ross, Kohn, J. Evans, Easter, Skinner, Guest. Replacements: Fuga, Lambert, Robson, Robshaw, Gomarsall, Williams, Luveniyali.
London Irish: Hewat, Ojo, D. Armitage, Mapusua, Tagicakibau, Hickey, Richards, Corbisiero, Paice, Rautenbach, Kennedy, Johnson, Thorpe, S. Armitage, Hala'ufia. Replacements: Lea'aetoa, Coetzee, Casey, Fisher, Thompstone, Hodgson, Seveali'i.
Referee: Dean Richards (RFU)