Charlie Christie's men were trying to bounce back from the disappointing defeat against Falkirk at the weekend, while the Buddies were aiming to build on their draw at Rangers.
Home midfielder Ian Black missed out after his red card shame on Saturday, so Russell Duncan took his place and Barry Wilson returned at the expense of Alan Morgan.
Visiting boss Gus MacPherson brought John Sutton back into the fray along with young midfielder David McKenna, and put veteran assistant player-manager Andy Millen and Ian Maxwell on the bench.
The first chance arrived when Graham Bayne intercepted a slack back-pass and drilled a low shot wide of the left post.
But after just five minutes, Bayne headed the Highlanders in front when he met an inviting Roy McBain cross from the right flank.
The Saints were denied by a brilliant one-handed save from Inverness keeper Mark Brown, which prevented McKenna netting from a Mark Corcoran cross on 10 minutes.
The lead was doubled on 21 minutes when Richard Hastings' delivery was smashed home in style from Dennis Wyness in the penalty box. This was the striker's first SPL goal since last February.
As Caley Thistle stepped up another gear, Duncan's searing shot flashed just wide from fully 30 yards.
The hosts would have been satisfied with their deserved 2-0 interval lead. Saints' Kirk Broadfoot tried to fire his team back into the game seven minutes after the break with a 20-yarder, but Brown was equal to it.
Then Bayne burst forward at the other end and his cross was met by John Rankin, whose drive was well gathered by Tony Bullock.
Bayne, who was in terrific form, then shot downwards from a Barry Wilson assist but Bullock held it.
Then, with 14 minutes to go, Broadfoot steered home a free header from a Richard Brittain corner to give the Buddies an unexpected lifeline.
Only an outstanding Brown save moments later prevented a net-bound Garry Brady header from levelling the scores.
As Inverness were left clinging on, a Corcoran strike clipped the top of the crossbar.
Wilson's handball on the edge of the area allowed the Paisley men a great late chance, but Broadfoot fired the free-kick over the top.