Mihajlovic was diagnosed with Leukaemia back in 2019 and successfully underwent treatment but the disease resurfaced earlier this year.
The former Yugoslavia international nonetheless continued with his managerial duties with Bologna but was sacked in September after a difficult start to the season.
Mihajlovic played for several Serie A clubs including Lazio, AS Roma, Sampdoria and Inter Milan.
He also managed Fiorentina, AC Milan, Sampdoria and the Serbia national team.
Lazio, where Mihajlovic won the Serie A title as a player, said in a statement: "Lazio mourns the passing of Sinisa Mihajlovic: a great Lazio man, a warrior on the pitch and in life. His courage on the pitch was second only to that shown in the face of a serious illness, which never weakened him in spirit and temper.
"An indelible trace in the history of Lazio will remain of this fighter with a big heart, not only for having been champion of Italy, but for the message of hope in the face of the difficulties that he was able to represent up to the last moment of his life.
"We will remember him as he deserves, with the infinite embrace of his team and his people. Our deepest condolences to the family."
A Serie A statement said: "Lega Serie A is deeply saddened by the passing of Sinisa Mihajlovic, an icon of football and life.
"His pure class as a footballer and coach, his strength and his humanity are an example that leaves an indelible mark on Italian and world football."
