Ohtani's solo shot in the third inning off Marco Gonzales soared into the top deck of right field at T-Mobile Park. The Angels' two-way phenom is the sixth player to reach the upper deck of the right-field seats since the stadium opened in 1999, according to the Mariners.
MLB's Statcast projected the homer at 463 feet. "That ball was far. It said 463. That can't be 463,'' Angels manager Joe Maddon said after the game.
Ohtani's blast left a buzz through the venue and caused a couple of fans sitting alone in that section of the stadium to duck as the ball drew closer. It landed above the fifth row of seats before hitting a concrete wall and ricocheting back down into the lower levels.
The Angels dugout erupted in excitement and disbelief after Ohtani's left-handed swing. Justin Upton put his hands on his head in shock when it landed in the upper deck.
"I think that Statcast was wrong. I think that ball was well over 500 feet. ... I know we talk about Shohei all the time, but we're not talking about them enough. It's just incredible,'' Angels starter Alex Cobb said.
The homer put the Angels up 3-0 but Seattle tied the score in the seventh inning before breaking it open with a Mitch Haniger grand slam in the eighth to give the Mariners a 7-3 victory.
"He's got that kind of power, that kind of talent,'' Seattle manager Scott Servais said of Ohtani. "But at end of the day it's only worth one, and [Hangier's] was worth four. I liked [Haniger's] a little bit better even if it didn't go quite as far."
Ohtani's home run, his lone hit in the loss, was his 16th in the past 21 games, making him just the seventh player in MLB history to hit that many in a 21-game span within a single season. He joins Barry Bonds, Giancarlo Stanton, J.D. Martinez, Kyle Schwarber, Mark McGwire and Sammy Sosa.
Ohtani is also the first player since Albert Pujols in 2006 to hit 33 or more homers in his first 82 games of a season. He's on pace for 61 this season.
The Associated Press contributed to this report.