Euros was cast into doubt as he was found to have a heart defect.
Coming back from a game in Rome he suffered an ischemic stroke that required surgery to repair a hole in his heart.
Thereafter he faced a long and uncertain wait on the sidelines to recover before doctors would give him the all-clear to return to the field.
It was a tragic blow for a player who had long struggled with a ballooning waistline, fitness issues, temperament problems and the lack of faith from national team coaches.
Marcello Lippi had overlooked him entirely for the 2010 World Cup campaign, while the 29-year-old has rarely enjoyed long stints as a first team regular since making his debut in 2003.
But two years ago, with Cassano showing great form for Sampdoria and a new coach in Cesare Prandelli leading the national team, suddenly the troubled but talented striker found himself an integral part of the Italy set-up.
Prandelli even said he wanted to base his side around Cassano and the boy from Bari seemed rejuvenated by responsibility and respect.
Yet that fateful night in October looked to have cost him the chance to make it to the Euros.
Many doubted whether Cassano could remain disciplined enough during the long lay-off to give himself a fighting chance of making the squad when passed fit.
As it happened, he had to wait until April to be given the all-clear and when he did come back, his path to first team football was blocked by Milan's preferred front-pairing of Zlatan Ibrahimovic and Robinho.
Yet when he returned to action, he at least seemed to be sporting a physique that resembled a professional athlete, something that had not always been the case during his chequered career.
Deprived of regular first team action, Prandelli was forced to bring him only half fit to the tournament.
And yet such is the strength of Prandelli's man-managment and resource allocation that he never intended to play Cassano over a full match.
He has started his star forward in every single game and told him to run until he dropped, after which he made way for fresher legs.
Against Germany in the 2-1 semi-final victory, he did exactly that.
"It was Antonio's best match in terms of intensity and tempo. He ran, he fought, he realised he could be important even though he only had 50 minutes in his legs," said Prandelli.
"But it was 50 minutes of great quality."
Cassano it was who found space on the left, pivoted to escape the attentions of Mats Hummels and Jerome Boateng before picking out the head of Mario Balotelli six yards out with a pinpoint cross from his weaker left foot.
The Milan forward was energetic and involved, constantly finding space between Germany's defence and midfield or drifting out wide where another cross for Riccardo Montolivo should have resulted in a goal.
It was a performance that helped ensure Germany never settled and found themselves 2-0 down and chasing the game long before they could build up a head of steam.
The man they call "Fant-antonio" in Italy may not be able to survive an epic encounter to the end but his telling interventions during his shortened stints on the pitch have had a magical affect on Prandelli's Italy.
Now the coach will be counting on the former bad-boy to become the man of the moment and fire the Azzurri to Euro glory against Spain on Sunday.