The rubber-armed Wakefield, who played 17 seasons for Boston after two years with the Pittsburgh Pirates, is third on the Red Sox list for career wins (186), six short of the team record held by Cy Young and Roger Clemens.
Also known for his charitable work, Wakefield was given MLB's Roberto Clemente Award in 2010, presented to the player who best reflects the spirit of giving back to the community, for his work with charities assisting children in need.
"Tim's kindness and indomitable spirit were as legendary as his knuckleball," said Red Sox Principal Owner John Henry.
"He not only captivated us on the field but was the rare athlete whose legacy extended beyond the record books to the countless lives he touched with his warmth and genuine spirit."
Drafted by Pittsburgh in 1988 as a first baseman, Wakefield decided his odds of reaching the majors were better as a pitcher and developed the tricky knuckleball delivery to speed his progress.
The knuckleball is a pitch delivered with fingers dug into the ball in order to release it without imparting spin.
Not only is the speed of the delivery cut by about one-third, but the floating ball is affected by air conditions and currents that can drastically alter its flight. It can be as hard for a catcher to corral as for a batter to hit.
Armed with the beguiling pitch, Wakefield found himself on the fast-track to the majors and joined the Pirates for the 1992 season and posted an 8-1 record. But then the right-hander lost control of the pitch and was cut by Pittsburgh.
After a standout season for Boston's Triple-A minor league team, Wakefield was a hit with the Red Sox in 1995, going 16-8 with a 2.95 ERA in what might have been his best season.
Despite never quite reaching those heights again, Wakefield remained a fixture with Boston where he won World Series titles in 2004 and 2007 and doubled as a relief pitcher over the years.
Wakefield retired from in 2012 with a 200-180 career record and 4.41 earned run average.
"We are deeply saddened by the loss of Tim Wakefield, one of the most unique pitchers of his generation and a key part of the most successful era in the history of the Boston Red Sox," said MLB Commissioner Robert Manfred.
"Tim's knuckleball allowed him to excel as a rookie with the Pittsburgh Pirates in 1992. In 1995, he began a 17-year tenure in Boston, where he made a mark that will be remembered forever."
