Diego Milito was a late injury victim, but Andrea Stramaccioni opted for a two man attack, so new signing Tommaso Rocchi started from the bench. Samir Handanovic and Giovanni Pasquale faced their former clubs.
Di Natale almost opened the scoring on 14 minutes. The veteran forward got in behind Walter Samuel and shot from the byline, but the angle was too tight and the ball went over.
Inter were denied a penalty ten minutes later. Antonio Cassano threaded through for Rodrigo Palacio, Maurizio Domizzi made minimal contact with a hand on the shoulder and the frontman theatrically went down. Domizzi was the last man, but the referee rightly booked Palacio for diving.
Moments later, Di Natale thrashed a free kick against the bar from 35 yards, with Handanovic rooted to the spot. Ten minutes before the break, Handanovic fisted clear to prevent Domizzi making contact with a header.
Javier Zanetti rolled back the years, expertly turning two players before continuing his run into the box. Unfortunately for the veteran, his pull back for Cassano was intercepted and the danger was cleared.
Zeljko Brkic tipped wide a Walter Gargano drive, then punched clear from Cassano seven minutes before the break. Di Natale swung another free kick from a similar distance over in the final action of the half.
Inter wasted a golden chance to score five minutes after the restart. Cassano dribbled into the box, Palacio laid the ball off to Jonathan, who inexplicably missed, just yards from goal. It was a miss to rival Marko Livaja's against Genoa before Christmas.
The visitors continued to go forward, but Brkic got down to save a low shot from Guarin and foiled Palacio with a one handed stop.
Just after the hour, Guarin rolled across for Palacio in the box, but the frontman slipped upon shooting and the ball went wide. It proved to be a costly miss as Udinese soon opened the scoring.
From a quick break, Andrea Lazzari sent Di Natale clear and the forward directed a right footed shot past the outstretched Handanovic into the bottom left corner.
Inter self destructed and Juan Jesus was given a second booking for treading on Muriel. Play was temporarily halted, while Muriel recovered and rejoined the match.
Muriel doubled the home side's advantage 15 minutes from the end. Dusan Basta split the defence and Muriel sent a powerful shot past a hapless Handanovic who had ran out to try and close the gap.
Di Natale rubbed salt into the wounds with Udinese's third. Lazzari was again the architect, this time with a low cross which Toto stabbed home from a predatory position in the box. In truth, it was poor marking from the Nerazzurri, but their heads had dropped and the game was well and truly over.
Udinese: Brkic; Heurtaux, Danilo, Domizzi; Basta, Pereyra, Allan, Lazzari, Pasquale; Muriel, (Maicousel 81) Di Natale (Ranegie 88)
Inter Milan: Handanovic; Samuel, Cambiasso, Juan Jesus; Jonathan, (Rocchi 78) Zanetti, Gargano, (Duncan 74) Guarin, Pereira; Cassano, (Silvestre 82) Palacio
Goals: Di Natale 64, 79 (U) Muriel 75 (U)
Sent off: Juan Jesus 65 (I)