Riccardo Meggiorini gave Novara a first-half lead and Marco Rigoni scored twice in the last five minutes as Novara won for the first time since returning to Serie A after a 55-year wait.
Esteban Cambiasso pulled one back for Inter whose captain Javier Zanetti was making a club record 757th appearance.
Inter have taken only one point from three Serie A games this season under new coach Gasperini and also lost at home to Turkey's Trabzonspor in the Champions League last week having already been beaten by AC Milan in the Italian Super Cup.
Gasperini has never managed a top side before and his future is already the subject of speculation, with president Massimo Moratti saying he would prefer a four-man defence to the coach's much-criticised three-man formation.
Novara could have scored in the first minute when Cristian Chivu's misplaced pass went to Meggiorini but he fired over.
Meggiorini made no mistake in the 38th, however, finishing a counter-attack with a left-foot shot after Inter again lost possession in midfield.
Inter never looked confident, with Wesley Sneijder and Diego Forlan being substituted midway through the second half.
Their frustration was best summed by a yellow card for diving shwon to central defender Lucio.
It got worse in the 85th minute when Takayuki Morimoto was bundled over in the area by Andrea Ranocchia, who was sent off, and Rigoni fired in the penalty.
Cambiasso pulled one back in the 89th, the first time Inter had threatened, only for Rigoni to score again in added-time by slotting in a rebound after more mayhem in the visiting defence.
