The announcement was made by Lakers General Manager Mitch Kupchak on its website. A search for a replacement will begin immediately, the team said.
D'Antoni replaced Mike Brown on Nov. 12, 2012, and had a 67-87 record in his two seasons with the Lakers. He has a career record of 455-426.
"Given the circumstances, I don't know that anybody could have done a better job than Mike did the past two seasons," said Kupchak. "On behalf of the Lakers, we thank Mike for the work ethic, professionalism and positive attitude that he brought to the team every day. We wish him the best of luck."
The injury-plagued Lakers were 27-55 this season, their worst campaign in more than 50 years. Los Angeles missed the playoffs for only the third time in 38 years.
D'Antoni had one year left on his contract, but wanted the Lakers to pick up his option year for 2015-16 to have any chance of success. The Lakers apparently refused, leading to D'Antoni's resignation.
Shortly after the announcement was made, Magic Johnson tweeted: "Happy days are here again! Mike D'Antoni resigns as the Lakers coach. I couldn't be happier!"
The Associated Press contributed to this report.
