Team spokesman John Black confirmed D'Antoni's resignation, ending the brief tenure of the Lakers' fourth head coach in less than three years.
D'Antoni went 67-87 after taking over the Lakers early in the 2012-13 season. He replaced the fired Mike Brown, who lasted just 71 games after replacing 11-time NBA champion coach Phil Jackson in 2011.
The injury-plagued Lakers were 27-55 this season, their worst campaign in more than 50 years and the second-worst winning percentage in franchise history.
With Kobe Bryant, Steve Nash and Pau Gasol sitting out large chunks of the season while the Lakers lost an NBA-worst 319 man-games to injuries, the 16-time NBA champion franchise missed the playoffs for the first time in nine seasons and only the third time in 38 years.
"Given the circumstances, I don't know that anybody could have done a better job than Mike did the past two seasons," Lakers general manager Mitch Kupchak said. "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 62-year-old 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.
D'Antoni walked away from a $4 million payday for next season, although he may receive a portion of that money as severance.
A phone message left for D'Antoni wasn't immediately returned.
Despite the Lakers' injuries on a roster consisting mostly of players on one-year contracts, Los Angeles fans largely directed their anger during a rare down season toward D'Antoni. Lakers great Magic Johnson, who was sharply critical of D'Antoni's coaching style, hailed the news on his Twitter account.
"Happy days are here again!" Johnson tweeted. "Mike D'Antoni resigns as the Lakers coach. I couldn't be happier!"
D'Antoni also has coached the Nuggets, Suns and Knicks. He reached two Western Conference finals with Nash in Phoenix before having much less success in New York.
"Whenever a coach isn't there anymore, for whatever reason, all of us in the fraternity feel badly," San Antonio coach Gregg Popovich said after the Spurs' playoff victory over Dallas. "He is a heck of a coach and heck of a guy. You always feel badly when something like that happens. I just hope that what he wants is going to be what happens for him. He is a special guy."
D'Antoni's signature up-tempo style of play seemed an odd match from the start with the aging, ball-dominating Bryant and the Lakers, who ran Jackson's deliberate triangle offence to perfection.
Lakers owners Jerry and Jim Buss curiously chose D'Antoni to replace Brown over Jackson, who strongly contemplated a return for a third stint on the Los Angeles bench. Jackson became the president of the Knicks in March.
Kupchak said he will begin the search immediately for the Lakers' fifth head coach since 2011 — including Jackson, who walked away from the team after falling short of a third consecutive championship.
D'Antoni's departure will allow the Lakers' franchise overhaul to begin in earnest after their worst season since 1957-58 back in Minneapolis. Los Angeles missed the post-season for just the second time in the 17-season career of Bryant, who occasionally clashed with D'Antoni.
The Lakers have a top-10 pick in a strong draft and just three players under contract for next season, including Nash and Bryant. The fourth-leading scorer in NBA history will make more than $48 million over the next two years.
A coaching change also might make the Lakers more attractive to Gasol, an unrestricted free agent who intimated he wouldn't consider returning if D'Antoni still coached the team. Kupchak has said the Lakers are very interested in re-signing the 7-foot Spaniard, one of the top available free agents.
"There would have to be significant changes," Gasol wrote in Spanish on his personal blog recently. "I've never concealed the fact that D'Antoni's style doesn't suit my game. Everybody knows this. I don't know if my decision will be swayed by whether Mike stays or leaves. Obviously, the coach is a very important factor for any team."
After joining the Lakers on short notice last season, D'Antoni was unable to assemble a contending team immediately around Bryant and Dwight Howard, who struggled to embrace the pick-and-roll game so important to D'Antoni's offence.
Los Angeles won 45 games last season despite its awful start under Brown. But the Lakers lost Bryant to a torn Achilles tendon late in the regular season before getting swept out of the first round by San Antonio.
Howard left the Lakers as a free agent last summer, fleeing to Houston for less money to escape the Lakers' drama and high expectations.
Bryant played in just six games this season after breaking a bone near his knee in December, and Los Angeles never had a consistently competitive team in his absence. Nash also missed most of the season with various injuries, but the 40-year-old point guard hopes to play again next season.
D'Antoni realized he would take the blame for the Lakers' woes this season, and the veteran coach seemed comfortable with the prospect when the team packed up for the summer.
"Every coach should be under scrutiny," D'Antoni said two weeks ago. "Some coaches get fired even after the best years they've ever had. ... There's always things we could have done better, and it's easier with hindsight. Things don't always go smoothly. For the most part, our guys were very competitive. For us, there are some silver linings in there, but in hindsight, it's disappointing for everybody."