Andrea Stramaccioni's men never looked comfortable as they produced a pedestrian display that saw the Serie A strugglers come out on top, thanks to strikes from Innocent Emeghara, Alessio Sestu and Alessandro Rosina.
The visitors' only reply came from Antonio Cassano and their misery was compounded by Cristian Chivu's second-half sending off.
The Nerazzurri handed debuts to their two January acquisitions Ezequiel Schelotto and Zdravko Kuzmanovic as they went in search of their first away success since their triumph over Juventus back in November.
Stramaccioni’s side once again took the field with a back three and Siena looked to exploit their opponent’s lack of width early on, as January loanee Innocent Emeghara failed to make the most of a clean break down the left.
Gianluca Pegolo has been a busy man in the Bianconeri goal so far this season and he was forced into a couple of fine stops as Inter looked to break the deadlock early on.
He was forced into a flying save by Fredy Guarin after the Colombia international let fly from 30 yards and moments later he was called into action once more to beat away Juan Jesus' acrobatic effort.
A whirlwind five-minute spell then saw the hosts seize the initiative as the teams shared three goals in a matter of moments.
Matteo Rubin broke down the left for the hosts yet again and with no Inter player in the middle able to prevent the ball from falling at the feet of Emeghara, he opened the scoring with the simplest of tap-ins.
The hosts’ lead barely lasted a minute though, as Inter new boy Kuzmanovic picked out Antonio Cassano on the edge of the area and his low, curled cross evaded Yuto Nagatomo in the centre and nestled in the far corner for the Italian’s first goal since October.
The Nerazzurri’s parity did not last long though, as they were undone on 25 minutes by a moment of magic from Alessio Sestu. Once again Inter allowed their opponents space on the left and Rosina was able to pick out Sestu on the edge of the area, who took a touch before sending a curling effort beyond Samir Handanovic and into the top corner.
The away side looked to claw themselves level before the break but Kuzmanovic’s deflected effort landed just wide of the post and Cassano’s appeals for a penalty were dismissed as the sides entered the dressing rooms level at the break.
The game swung in Siena’s favour just 10 minutes into the second half when Inter were reduced to 10-men and the hosts were given the chance to double their lead from the penalty spot.
Despite changing to a 4-4-2 formation at the break, the visitors were caught out by a long ball over the top which put Emeghara clean through, and the Switzerland international’s surge on goal was halted by Cristian Chivu’s rash challenge inside the area.
The Romanian was sent off and Rosina dispatched the penalty into the bottom corner to give his side a commanding grasp on the game.
Siena sat back on their lead and invited the 10-man visitors onto them in the final quarter, but despite Guarin going close with a free kick and Cassano rattling the crossbar with an effort in a crowded penalty area, the home side were able to hold on to complete a famous double.