The Mozambique-born striker scored 733 goals in 745 professional matches and is considered as one of the sport's all-time greats.
Eusebio enjoyed an extremely successful career in both domestic and international competition, winning 11 Portuguese titles and one European Cup crown at Benfica.
He finished as Portugal's top scorer at the 1966 FIFA World Cup, helping them to a third-place finish, and scored a total of 41 goals in 64 games for his country.
The 1965 European Footballer of the year retired in 1979 after spells with a number of sides in America and Canada.
Eusebio was reportedly admitted to hospital several times over the last year as his health deteriorated.
Lisbon outfit Benfica expressed their shock at the news of his passing.
"The unexpected news caught us by surprise and in a brutal way," a statement on Benfica's official website read.
"There are some men who should never leave. Eusebio da Silva Ferreira has died – a major reference of Benfica and Portugal.
"We will always remember his talent, the example and character of a man who marked Portuguese football and became a reference in the world of football. Let us recall his joy for life, his simplicity and straightforwardness.
"The life of Eusebio is a heritage for all those who love football. Benfica was his home. Eusebio was a tireless professional for his club, someone who always made Benfica more than his club, but rather his home and his family.
"The best way to pay homage to Eusebio is to continue to fulfill his dreams and ambitions. The memory and legacy of Eusebio stay with us."