Worthington, whose reign as manager ends tonight, was forced to send out a youthful side due to a series of withdrawals that left him two substitutes short and Cassano took full advantage, producing two wonderful goals to finish the campaign with six.
The Group C winners' third left a sour taste for another departing Northern Irishman, as veteran goalkeeper Maik Taylor's misunderstanding with Gareth McAuley resulted in a demoralising own-goal.
Worthington has been hampered throughout qualification by injuries and suspensions, so it seemed cruelly fitting that his final match came with his resources stretched even further than ever.
A total of 10 players originally picked for his 23-man squad were missing here - Craig Cathcart's knee giving way in the morning as he joined a list of absentees including Aaron Hughes, Jonny Evans, Chris Brunt and Kyle Lafferty.
In their place, Worthington promoted a host of young players in the shape of Ryan McGivern, Oliver Norwood, Andrew Little and Jonny Gorman.
At the other end of the spectrum, 40-year-old Taylor was handed the captaincy on what will surely be a farewell appearance and David Healy equalled Mal Donaghy's outfield record with a 91st cap.
With just seconds on the clock, Little made a daring charge toward the Italy box, but he could not find a final touch to the waiting Healy.
Northern Ireland's best hopes were of a lapse in concentration from their already-qualified opponents.
Little almost beat Buffon to a long free-kick as his defenders watched, while a poor backpass nearly handed Healy a one-on-one.
Giorgio Chiellini went close from a 19th-minute corner when he headed wide at the far post but when the goal did come, it was an altogether classier affair.
Daniele De Rossi lofted a delightful through ball to wrongfoot the back four, with Cassano the target.
The AC Milan forward let the ball drop over his right shoulder and volleyed home from eight yards.
The goal brought out some Italian party tricks and Sebastian Giovinco, Cassano and Alberto Aquilani soon started injecting some flair.
Northern Ireland, thanks to some brave defending, did well not to concede again within minutes.
Indeed, with 27 minutes gone they desperately close to an unlikely equaliser, Gorman finding McGivern with a flat free-kick and the 21-year-old's header drawing a fine low save from Buffon.
From then until half-time it was all Italy.
Andrea Pirlo's chip gave Cassano the sniff of a second but this time he could not repeat his earlier finish and the striker also had a penalty appeal against Ryan McGivern rejected.
Giovinco, meanwhile, had three chances before the break, lifting the first over the crossbar after turning Lee Hodson and then hitting tamely at Taylor from 12 yards. The third, an athletic overhead kick that flew just over, was the last action of the first half.
Italy held possession for a matter of minutes from the restart, with Aquilani's hopeful drive poor reward for the build-up.
Healy scrapped doggedly in a thankless lone striker's role but did manage to create a half chance for Steven Davis in the 49th minute only for the midfielder to run out of steam as he bore down on goal.
Four minutes later it was 2-0 to Italy, Cassano lifting the tempo of a sedate move by taking aim and finding the bottom corner with a precision strike from 20 yards.
The striker was replaced soon after, denied the chance of a hat-trick, and Northern Ireland breathed a sigh of relief.
Gorman and the tireless Davis worked hard in midfield to try and bring their side back into the game and with 67 minutes gone substitute Warren Feeney had a glorious chance.
Davis' cross from the left evaded Chiellini and bounced invitingly for the Plymouth striker, who had been on the pitch a matter of moments following Healy's departure.
But with only Buffon to beat, he launched his shot high over the crossbar.
Taylor, unattached since his release by Birmingham, showed he was still sharp with a goal-saving parry from Riccardo Montolivo but there was further disappointment to come with 16 minutes remaining.
Federico Balzaretti had stolen in on the left of the penalty area and crossed along the face of goal, only for McAuley to bundle the ball past Taylor as both men attempted to clear.
The remaining interest came from the bench, with Preston's Conor McLaughlin handed a debut by Worthington and goalkeeper Morgan de Sanctis sent on by Cesare Prandelli at the venue where he started his club career.
While Italy will head to the Euro 2012 finals in good spirits, Worthington will leave his post with a fourth straight defeat.