After a poor first half, Ryan Christie headed home just before the hour mark for the hosts before Greg Tansey's strike in injury time sealed all three points at the expense of this season's William Hill Scottish Cup finalists.
Inverness manager John Hughes made two changes from the side that had lost 2-1 at Motherwell in midweek.
Christie and James Vincent came into the starting line-up with Marley Watkins dropping to the bench and Gary Warren not involved.
With the Scottish Cup final less than a week away, St Johnstone boss Tommy Wright opted to make wholesale changes following Wednesday night's dramatic comeback in their 3-3 draw with Celtic.
Only Alan Mannus, Steven Anderson, Gary Miller and Michael O'Halloran kept their places with Gary McDonald, Scott Brown, Lee Croft, Tim Clancy and top scorer Stevie May all amongst the substitutes, and Frazer Wright and Paddy Cregg missing out.
Caley Thistle created the first real opening of the match only for Billy McKay to see his strike at goal deflected over after a quick free-kick.
St Johnstone responded almost immediately, O'Halloran's run causing problems for the home defence, but his low effort from 18 yards was blocked away to safety by Inverness goalkeeper Dean Brill.
Opportunities were few and far between, but Christie at least forced Mannus into a save, albeit a simple one, from David Raven's cross.
Mannus was then called upon again moments later, again saving comfortably as Tansey tried his luck from distance.
After a lacklustre opening 45 minutes, the second half started with more purpose, O'Halloran drawing a fine tip over from Brill at his near post after firing one in from an angle 12 yards out.
Mannus then had to look just as lively at the opposite end, getting a touch to Raven's neat flick from Vincent's low cross.
He could do nothing, however, to prevent Caley Thistle from opening the scoring in the 59th minute.
Aaron Doran let fly from the angle of the 18-yard box and despite Mannus managing to parry away the shot, Christie nipped in to head home the rebound for his third goal in three starts for Inverness.
Caley Thistle almost doubled their advantage 10 minutes later. Christie's pass put McKay in on goal, but Mannus was out quickly to block, before Brian Easton blocked Doran's goalbound effort from the loose ball.
St Johnstone introduced top scorer May but it was all Inverness, Watkins' stinging drive rising just over the crossbar.
The points were made safe in the first minute of stoppage time, a swift counter-attack by Caley Thistle ending up with Tansey blasting an unstoppable strike from 14 yards into the top corner.