A well-worked try from Jason Robinson lit up a dull first-half where the only other scores came from the boot of Barry Everitt and Charlie Hodgson.
Sale came to life after the break with tries from Daniel Larrechea, Sebastien Chabal and Mark Cueto.
Cueto's late score saw the England man go over for his seventh try in seven matches - a new Premiership record.
Brian Smith, London Irish coach: "We didn't control the ball well enough and they out-muscled us in the tackle," said Smith.
"Fair play to Sale, they have a very threatening backline and they took their opportunities well."
London Irish have only won one of their three opening games of the Guinness Premiership season.
Sale: Larrechea, Cueto, Taylor, Seveali'i, Robinson, Hodgson, Courrent, Sheridan, Bruno, Turner, Jones, Schofield, White, Lund, Chabal.
Replacements: Ripol for Larrechea (51), Todd for Taylor (78),Wigglesworth for Courrent (78), Stewart for Turner (60), Day for Schofield (70), Lobbe for White (75), Titterrell for Lund (63).
London Irish: Armitage, Staniforth, Penney, Catt, Bishop, Everitt, Hodgson, Hatley, Flavin, Skuse, Strudwick, Roche, Magne, Dawson, Murphy.
Replacements: Geraghty for Catt (70), Willis for Hodgson (62), Collins for Hatley (66), Tait for Flavin (62), Hardwick for Skuse (40), Kennedy for Roche (70), Gustard for Magne (43).
Att: 7,246
Referee: R Debney (RFU)
MMIX
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