The former Scotland striker guided home the opener in the 39th minute and soon took advantage of some slack defending to head in another from a tight angle.
Motherwell came from two goals down to win against Hibernian last weekend and Bob McHugh, who netted the winner at Easter Road, again came off the bench and scored, but St Mirren held on.
The visitors began zipping the ball around but they almost conceded from John McGinn's 19th-minute corner, when Jim Goodwin managed to steer the ball on target from beyond the far post but Tom Hateley cleared off the line.
Well soon went close when Nicky Law hung a cross to the back post following a short corner and Shaun Hutchinson headed towards the top corner, but Craig Samson produced a wonderful reaction save to claw the ball out.
Motherwell were leaving gaps at the back and Thompson made them pay with a clever finish from six yards as he swept home Jon Robertson's centre.
Motherwell were then undone by a counter-attack. Some tidy play from McGinn gave Gary Teale the chance to send over a deep cross from the right. Hateley failed to get off the ground and Thompson rose to head the ball over Darren Randolph and in off the far post.
McHugh came on and soon got a chance when he met Humphrey's cutback, but Goodwin threw himself in the way of the shot to prevent a goal.
The striker then had a better chance when he latched on to a ball over the top but blasted just over from 15 yards.
McHugh soon got Motherwell back in the game when he fired a left-footed shot in off the bar from similar distance after good work from Henrik Ojamaa on the left, yet it was too little, too late.