The move came one day after the disappointing Cavs (16-33) lost at home to a Los Angeles Lakers team that finished the game with four healthy players and one who was allowed to keep playing with six fouls.
The Lakers had lost seven straight, 13 of their last 15 and 19 of their last 22 prior to Wednesday.
David Griffin, who joined the franchise as vice president of basketball operations in 2005, was named acting general manager.
Cleveland has lost six straight and eight of its last nine and went 80-199 while Grant was GM.
Grant, who joined the organization in 2005, took over in 2010 when Danny Ferry resigned and was immediately faced with rebuilding a team that lost LeBron James.
The Cavs went 19-63, 21-45 and 24-58 in Grant’s first three seasons, which were spent stockpiling high draft picks and acquiring young talent, but many of his young players have not panned out.
This was supposed to be the season Cleveland made a quantum leap and qualified for the playoffs, but that has not materialized.
“We have severely underperformed against expectations,” owner Dan Gilbert said in a statement. “Just as this is completely unacceptable to our loyal and passionate fan base, season ticket holders and corporate partners, it is also just as unacceptable to our ownership group.”