Riccardo Meggiorini put the home side in front in the 38th minute before a penalty from Marco Rigoni four minutes from the end gave them a two-goal cushion with the Nerazzurri reduced to 10 men with Andrea Ranocchia sent off.
Esteban Cambiasso pulled a goal back for Inter in the last minute, but Rigoni completed the scoring in stoppage time to give Attilio Tesser's side their first win since returning to the top flight.
Inter, meanwhile, have yet to win a game all season and, with just one point from their first three games, they could drop to the foot of the table after the remaining midweek fixtures in Serie A, while Gasperini may not be around for their trip to Bologna on Saturday.
Meggiorini almost gave the home side a dream start within 60 seconds when he pounced on a wild pass across goal from Cristian Chivu, but the Novara striker's shot skimmed off the face of Inter goalkeeper Julio Cesar and over the crossbar.
From the resulting corner, Rigoni's curling cross evaded everybody in the centre of the six-yard box except Chivu, who made up for his earlier error with a goalline clearance.
Novara continued to take the game to their illustrious opponents and deservedly took the lead in the 38th minute.
Referee Mauro Bergonzi intelligently let play continue after Wesley Sneijder fouled a Novara player in the centre of the field and the ball arrived at Mazzarani on the left wing.
He slotted the ball through to Meggiorini, who drilled his shot into the far corner of Julio Cesar's goal.
Mazzarani spurned the chance to make it two in the 53rd minute when he raced through on goal, but was let down by his finish as his weak shot was saved by Julio Cesar's legs.
Inter's first real chance of the game arrived in the 76th minute when Cambiasso sent Giampaolo Pazzini in past the Novara defence, but he pulled his shot across the face of goal.
Moments later, Ranocchia pulled up with an ankle injury, but since Gasperini had used up all three of his substitutions, he was forced to grit his teeth and carry on.
And the end for him came prematurely in the 86th minute when he tugged Takayuki Morimoto inside the penalty area while trying to keep up with the Japanese forward, and he was sent off as a penalty was awarded.
Rigoni dispatched the spot-kick to send the home fans wild.
However, there were still a few minutes to play and a lapse in concentration at the back allowed Cambiasso to give Inter hope.
But it was only short-lived as Rigoni scored his second in stoppage time to seal the win after Julio Cesar could only parry Luigi Giorgi's shot.