Steven MacLean smashed home the only goal of the game after 38 minutes to hand Danny Lennon's side their seventh defeat in their last eight Scottish Premiership fixtures.
Goalkeeper Marian Kello was also replaced at half-time and replaced by deputy Chris Dillo after limping off with injury as salt was rubbed into the Buddies' wounds.
The Perth Saints - guided from the sidelines by Callum Davidson and Alex Cleland while boss Tommy Wright continues his recovery from gallbladder surgery - have now won four of their last five matches and claimed this win without talisman Stevie May.
Having confirmed a top-six spot for the third season in succession with their weekend win over Hibernian, St Johnstone took no chances with their top-scorer ahead of next month's William Hill Scottish Cup semi-final with Aberdeen.
The 22-goal striker dropped to the bench as he was rested alongside defender Frazer Wright and midfielder Gary McDonald.
Lennon's side, meanwhile, were short on confidence but that did not stop the Buddies boss naming the same starting XI who lost 3-0 to champions-elect Celtic on Saturday.
But morale will have dropped to an all-time low now with just seven games left to rescue an increasingly-alarming situation.
Yet St Mirren started with a decent tempo and they forged the first opening after eight minutes as John McGinn wriggled past Lee Croft before stinging the fingers of Alan Mannus.
A Steven Thompson header from the resulting corner skimmed the bar, but the visitors were almost let in by Marc McAusland's slip as James Dunne fired wide soon after.
But Lennon's men continued to be the side who set the pace, coming close again after 21 minutes when Conor Newton's deflected strike landed on the roof of Mannus' net.
St Mirren are second bottom of the table for a reason, though, and they offered St Johnstone another opening six minutes later as David Wotherspoon cut-back was slotted wide by Michael O'Halloran.
The Perth men were growing in confidence as they found space down St Mirren's left-hand side far too often but Lennon's team thought they had the opener when Darren McGregor met Kenny McLean's corner to the back post only to nod over.
However, it was the visitors who took the lead when Saints striker MacLean wandered free at the back post to volley home Wotherspoon's deep corner seven minutes before the break.
It was goal St Mirren could ill afford to lose. But their desperation got the better of Sean Kelly and Josh Magennis when both swung at fresh air just as a chance for an instant leveller dropped into the visitors' danger zone.
Matters only got worse for Lennon as he was forced into a change at the break as Kello limped off. Frenchman Dillo was sent on in his place, while the Buddies boss also hooked Newton as he hoped to gain some extra width by throwing on Gregg Wylde.
St Johnstone made a change too as Wright came on for Tim Clancy and the defender had to be on his toes early on to boot clear after Paul McGowan brought out a good save from Mannus, while Steven Anderson then came up with an important goal-line block to deny Magennis' header.
Wylde's introduction had made a difference as the St Johnstone back four was stretched wider than they liked but the final ball was too easy for the visitors to defend.
At the other end, the Dillo had to bail out his side as he blocked O'Halloran's near-post strike after the hosts were caught pushing up too far.
It should have been St Mirren who spent the final few minutes pushing for a leveller but again Dillo had to dig them out of a hole twice in the closing stages as his side surrendered another result in meek fashion.