The 33-year-old veteran of 46 internationals and two World Cup campaigns was signed by the Heart amid great fanfare in October.
It always shaped as a risky move by the A-League club and their coach John Aloisi as Grella had not played a competitive match since being let go by English Premier League outfit Blackburn 13 months earlier.
On joining the Heart, Grella underwent a tough rehabilitation campaign with his personal fitness instructor Tim Schleiger.
But the string of injuries that blighted the tail-end of a great career proved too much to overcome, with Grella understood to have torn a calf muscle in Saturday's 1-0 loss to the Western Sydney Wanderers.
"After 17 years of professional football my body has told me it's enough," Grella said in a statement.
"I need to thank John Aloisi and the club for giving me a final chance to continue as a professional.
"I felt the club's culture was the perfect place for me to be and it's frustrating I won't have the opportunity to contribute to it and to John's first steps as a coach."
Aloisi said the Heart had done the right thing in throwing a lifeline to Grella - even though his only outing in the red and white was as a 67th-minute substitute against the Wanderers.
"Vince has been a brilliant contributor to Australian football for a long time," said Aloisi, a long-time Socceroos' teammate of Grella.
"He deserved an opportunity to see if he could resurrect his career and we are proud that we were able to give him that chance.
"We always knew it was going to be a risk, but for me, it was certainly a risk worth taking."
Grella spent a decade playing in the Italian Serie A with the likes of Empoli, Parma and Torino before moving to Blackburn Rovers in England in 2008.
He was a key member of the Australian lineup at the 2006 and 2010 World Cups and had expressed some hope of returning to the international scene if warranted by his club form in Melbourne.
Heart chairman Peter Sidwell said the midfielder had done everything possible to get his body right.
"The club will always be grateful to Vince for putting his life on hold and sacrificing so much personally and financially in order to assist this club," Sidwell said.