كتب : Hatem Maher
The Nerazzurri had to do without Cameroon striker Samuel Eto'o, who is on away for Nations Cup duty, and suspended forward Mario Balotelli.
Left-back Cristian Chivu and midfielder Esteban Cambiasso were also missing due to injury.
Siena's in-form striker Massimo Maccarone stunned the home crowd with a thunderous shot that left Inter keeper Julio Cesar with no chance after 18 minutes.
Diego Milito leveled the score six minutes later when he cut inside his marker and drilled a low shot into the bottom corner for his 11th league goal.
Wesley Sneijder put Inter in front with a superb curling free kick on 36 minutes but midfielder Albin Ekdal restored parity moments later.
Maccarone scored his second of the night in the 64th minute to give Siena a 3-2 lead before Inter left it late to record a remarkable win.
Another free-kick from Sneijder with two minutes remaining and a strike from central defender Samuel in the additional time gave Inter all three points.
The defending champions are on top of the table with 45 points, 11 ahead of second-placed AC Milan who have two games in hand.