Nearest rivals Roma ensured the race went right down to the wire, doing what was required of them in a 2-0 win at Chievo, but Diego Milito's second-half goal in Tuscany proved decisive as the Nerazzurri secured a domestic Double and the second part of a potential Treble.
Having already beaten Roma in the Coppa Italia final, Inter will now look to conclude their season with a clean sweep of trophies by beating Bayern Munich in next weekend's Champions League final.
Heading into the final day of the season, Inter's mission was simple: beat Siena and win the title, regardless of what Roma did in Verona.
But they were made to work hard for victory and any fears that Siena, already relegated from the top flight, may not be entirely motivated disappeared soon after kick-off when the hosts carved open Inter's defence, only for Albin Ekdal to poke wide from a great position.
The reigning champions recovered quickly and set about their task, although they were initially frustrated by a combination of some poor finishing, a resolute goalkeeper and the woodwork.
Mario Balotelli volleyed wide on 13 minutes before Milito prodded the wrong side of the upright after having sprung the Siena offside trap.
Gianluca Curci made the first of several important interventions soon after, the former Roma keeper denying Milito a close-range header with a big hand on 22 minutes.
Curci was again in action on the half-hour mark, repelling Walter Samuel's header before Ballotelli saw a brilliant volley from the edge of the penalty area crash against the crossbar.
Another Samuel header sailed over the bar before the end of the first half and at the break Inter found themselves with it all to do, with Roma having taken the lead in Verona - and with it provisional top spot.
The expected onslaught after the restart materialised, with Maicon and then Javier Zanetti bursting through to fashion goalscoring opportunities, the latter for Milito who prodded wide.
And it came as no surprise when Siena's resistance was finally broken on 57 minutes, Milito taking Zanetti's through pass in his stride before prodding past Curci.
Mourinho immediately replaced Balotelli with the more defensive-minded Dejan Stankovic as Inter looked to protect their lead - something at which they have proved extremely adept under Mourinho's stewardship.
With Siena offering little going forward - and Roma little hope - Inter played out the remainder of the game in comfortable enough fashion, although as full-time approached Julio Cesar allowed his nerves to get the better of him on two occasions, Inter's Brazilian keeper misjudging a cross before dropping one. Both times he got away with his errors.
Unlike his post-Champions League semi-final celebrations on the Nou Camp pitch, Mourinho initially chose not to join his players on the pitch at full-time, opting instead to offer one brief wave before disappearing down the tunnel.
The Portuguese, who has been linked with the Real Madrid job, later re-appeared to receive his medal and bask in the glory he deserved for leading Inter to the brink of history as the first Italian team to win a Treble.
In a sunny Verona, Roma enjoyed the better of the first half against Chievo and Francesco Totti could easily have grabbed a hat-trick before the deadlock was eventually broken by Mirko Vucinic.
The mercurial Giallorossi skipper fired against the post on 21 minutes before he stabbed wide five minutes later when he should have hit the target.
And when he missed his kick completely as the ball found him arriving at the far post and then had a goal disallowed for offside, it looked like it was going to be a frustrating afternoon for Claudio Ranieri's side.
But Vucinic eased any nerves with the opener on 39 minutes, the Montenegrin latching onto a through pass, taking a touch on his chest and firing past Lorenzo Squizzi.
That lead was extended soon after when De Rossi lashed into the top corner with a sensational strike from 30 yards out and at the break Roma's outlook was as sunny at the weather.
But Milito's goal in Siena soon changed that and the news, when it filtered through, inevitably had an effect on the game.
Roma, perhaps aware that Inter rarely blow a lead, allowed their morale to dip and the remainder of the second half was played without the same gusto in evidence before the break.
With relelgation matters already settled, the only other results of importance came in Genoa and Bergamo.
Sampdoria sealed fourth place - and a spot in the qualifying rounds of the Champions League - with a 1-0 win over Napoli, Giampaolo Pazzini getting the only goal of the game on 52 minutes.
That result left Palermo to settle for fifth place, despite the Rosanero's 2-1 win over Atalanta. Edinson Cavani's second of the game won the match in the final minute.
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