Sunday's race win followed the world champion's sprint success 24 hours earlier after nailing pole for both with a record lap time in qualifying.
His third win of the year after Portugal and Spain put further distance between him and Marco Bezzecchi, his closest rival in the standings who had to settle for eighth.
Jorge Martin took second with Johann Zarco completing the all-Ducati podium for the sixth round of the season at Mugello.
Bagnaia delighted his home fans by celebrating at a hastily erected picnic table, covered with a Ducati red tablecloth, in front of the stands.
Jack Miller got the run on Bagnaia off the grid but the world champion was back in front by turn two, the Italian showing he meant business after crashing last time out at Le Mans.
Martin emerged from the chasing pack to track Bagnaia, half a second splitting the pair.
Bezzecchi was struggling for pace on the Ducati of Valentino Rossi's VR46 team.
With 18 laps to go Marc Marquez crashed out.
The six-time world champion waved his arms in frustration at his fallen Honda as his wait for his first points in a race this term continued.
With Bagnaia setting sail for home, Miguel Oliveira joined Marquez in crashing out, Alex Marquez following suit with nine laps left.
Up front Bagnaia stretched his advantage over Martin to well over one second to take the chequered flag at his Ducati team's local track in the picture-postcard Tuscan hills.
The MotoGP circus moves on to Germany next weekend and then Assen the following week before taking a summer break.
RACE RESULTS
1. Francesco Bagnaia (ITA/Ducati) 41min 16.863 sec,2. Jorge Martin (ESP/Ducati-Pramac) at 1.067,
3. Johann Zarco (FRA/Ducati-Pramac) 1.977,
4. Luca Marini (ITA/Ducati-VR46) 4.625,
5. Brad Binder (RSA/KTM) 8.925,
6. Aleix Espargaro (ESP/Aprilia) 10.908,
7. Jack Miller (AUS/KTM) 10.999,
8. Marco Bezzecchi (ITA/Ducati-VR46) 12.654,
9. Enea Bastianini (ITA/Ducati) 17.102,
10. Franco Morbidelli (ITA/Yamaha) 17.610,
11. Fabio Quartararo (FRA/Yamaha) 17.861