Sale ensured London Irish's supporters left their new stadium for the first time disappointed as they recorded a hard-fought 21-13 Premiership victory.
Rohan Janse van Rensburg put Sale ahead as they dominated much of the first half, but Curtis Rona's try in stoppage time saw the sides level at the break.
Sale's Akker van der Merwe scored just after the restart before Paddy Jackson missed a penalty to close the gap.
AJ MacGinty's penalty sealed the win having been held up over the home line.
Sale stay fourth in the table while Irish drop to seventh after Harlequins beat Gloucester in Sunday's other Premiership match.
The game was London Irish's second at the new Brentford Community Stadium but the Exiles' first home match in the capital with supporters for 20 years following an extended period playing home games in Reading and the recent lifting of restrictions to allow some fans to return to sporting events during the coronavirus pandemic.
But it was Sale who impressed in the first half as they controlled much of the territory and possession.
Irish did well to keep their visitors out as the experienced Agustin Creevy held up Janse van Rensberg as he tried to cross the line, while the former Argentina hooker contributed a couple of important turnovers at the breakdown.
Having scored an early MacGinty penalty, Sale extended their lead when Janse van Rensberg went over after 22 minutes - Faf de Klerk took a quick tap penalty after a five-metre scrum collapsed and he set up the hulking centre to go over.
Sale missed a chance for a second try as Matt Postlethwaite knocked on as he stretched for the line after charging down Nick Phipps' box kick two minutes before half-time, and Irish took advantage as former Ireland fly-half Jackson produced a moment of skill to jink through the Sale defence and feed Rona after a stoppage-time lineout following a penalty.
A blistering start to the second half saw Van der Merwe get mauled over after a close-range line-out before Rona dropped a pass when he could well have gone on to score had he been able to gather it cleanly.
MacGinty's third penalty came after a sustained period of pressure on the Irish line which saw the United States fly-half held up by the spirited home defence with 20 minutes to go.
But as the half wore on Sale did well to snuff out any chance for Irish to create anything as Steve Diamond's side registered a second win from three games.
London Irish director of rugby Declan Kidney:
"We played a lot of good rugby and come away from the game with nothing.
"I think that we gave ourselves enough chances and on another day things will click into place, but we can only work on the things that we can control.
"I think there were a few little tackles when they managed to get their hand around and knock the ball down, and things like that, that probably weren't picked up as much as they could have been, but it's a game of tight margins.
"One of the reasons why I'm disappointed with the way the result went was having a crowd in because they were brilliant.
"They stayed with us and they really energised us."
Sale director of rugby Steve Diamond:
"We'd said at half-time that we'd only made a couple of errors in that first half and they were in the last minute.
"We just needed to keep getting field position - our line-out didn't function as well as I'd like, but the scrum was reasonably dominant.
"They're missing players, like we're missing players, but they'll knock a lot of sides over in their fantastic new home."
London Irish: Homer; Loader, Rona, Meakes, Hassell-Collins; Jackson, Phipps; Dell, Creevy, Kepu, Nott, Mahu, Cooke, Moore-Aiono, Rogerson (capt).
Replacements: Matu'u, Goodrick-Clarke, Hoskins, Curtis-Harris, Mafi, Meehan, Brophy-Clews, Parton.
Sale: L James; Yarde, S James, Janse van Rensburg, Hammersley; MacGinty, De Klerk; Morozov, Van der Merwe, John, Postlethwaite, Phillips, Wiese, Ross (capt), J-L du Preez.
Replacements: Langdon, Rodd, Cooper-Woolley, Ashman, Dugdale, Cliff, R du Preez, Solomona.
Referee: Christophe Ridley (RFU).