In the absence of Diego Milito, Goran Pandev started alongside Samuel Eto'o for Inter, while Ivan Cordoba returned for Marco Materazzi at the back. Udinese started with on-fire strike pairing Antonio Di Natale and Alexis Sanchez leading a 3-4-1-2 formation.
Sanchez had an early chance to extend his scoring run when meeting a right wing cross with a header above Ivan Cordoba, but he couldn't steer the ball goalwards. Moments later, Luca Castellazzi had Inter fans' hearts in their mouths when he spilled Maicon's miskick onto his own bar when attempting to push it out for a corner.
Despite the initial scares, it was Inter who struck first in the 16th minute. Thiago Motta won the ball on the right with a strong challenge before drawing Maurizio Domizzi and cutting the ball back to the edge of the area, where Dejan Stankovic took one touch before firing past Samir Handanovic.
Within four minutes the Serb very nearly doubled his tally as he forced a good save from Handanovic with a trademark fierce drive from 25 yards. It proved to be a vital intervention as Udinese hit back with an equaliser.
When a right wing corner wasn't immediately cleared, the ball was fed to Cristian Zapata's left foot 15 yards from goal. But nobody could have predicted that the centre-back would strike a sweet shot into the top of the net with his wrong foot, his effort escaping the dive of Luca Castellazzi on its way in.
Amazingly, Udinese were ahead on 25 minutes. Antonio Di Natale whipped a magnificent free-kick over the wall and into the bottom corner beyond Castellazzi's dive to net his 15th goal of the season.
The Friulani continued to cause trouble in the remainder of the first half, and though a Stankovic free-kick brought a decent save out of Handanovic, there wasn't an awful lot else for the home side to worry about before the half-time whistle.
Francesco Guidolin's side twice came close to extending their advantage just after the break. First Giampiero Pinzi broke the offside trap but Castellazzi managed to smother the ball, then Domizzi hit a stinging free-kick which stung the palms of the keeper as he pushed the ball wide.
The taste of the game turned somewhat bitter after Thiago Motta committed a rash foul on Sanchez, which brought about a coming together involving 15 or 16 players.
With the Friulani pressing hard, it was no surprise when they went 3-1 up on 69 minutes. After Inter had half-cleared an attack, Kwadwo Asamoah headed forward towards Maurizio Domizzi, who was played onside by Cordoba, and the centre-back managed to stab the ball home as he stretched to beat Castellazzi to the ball.
Trailing by two goals, the champions were never really able to fashion enough opportunities to scare Udinese as the home side held on with something to spare.
The result pushes Udinese to within a point of the Europa League spots, while Inter remain six points behind leaders Milan with their game in hand having now been squandered.