Del Negro compiled a 128-102 record with the Clippers in three seasons, guiding them to the playoffs in 2012 and 2013.
The Clippers finished the 2012-13 season with a franchise-high of 56 wins, including a 17-game winning streak, and were fourth-seeded in the Western Conference playoffs before falling 4-2 to the Memphis Grizzlies in the first round.
They held a 2-0 lead in the series before losing four games in a row to end their season.
The search for a new coach would begin immediately, the team said on its website.
"We would like to thank Vinny for everything he did during his three years with the organization," Clippers vice president of basketball operations Gary Sacks said in a statement.
"Vinny helped this team win a Pacific Division title and we greatly appreciate all that he and his staff helped us accomplish. This was a difficult decision, but we feel this is the best decision for our franchise moving forward."
In five seasons as a head coach with the Chicago Bulls and Clippers, Del Negro owns a 210-184 (.533) career record.