The crowd erupted as Thome hit his shot to left-center field. Thome pumped his right fist as he rounded first base and pointed to the crowd. He was mobbed by teammates when he reached home plate as the Phillie Phanatic (search) deliriously danced on the dugout with a "400" sign.
The fans gave Thome a standing ovation and he emerged from the dugout for a curtain call shortly before Pat Burrell followed with a solo shot.
Flashbulbs popped all over the park on every pitch as he dug in against Jose Acevedo. Fans gasped on several foul balls, thinking each swing would be the one.
Thome battled back from an 0-2 count to get it to 3-2, then crushed it. He's now 2-for-4 lifetime against Acevedo.
"It's an awesome thing," Thome said of his impending milestone before the game. "Looking back at all the work, all the time in the cage, I'll just enjoy it. I'll let it happen."
It was Thome's major league-leading 19th home run of the season and his 66th with the Phillies. Thome was tied with Al Kaline on the career list with 399.
Thome was likely to have the night to himself. Cincinnati's Ken Griffey Jr. was out of the lineup, giving him a better chance to hit his 500th home run at home in Cincinnati. Griffey hit his 499th homer Sunday.
Thome has become Philadelphia's most popular player thanks to his down-home charm and mammoth homers.
He signed a six-year contract as a free agent in 2002 after 12 years in Cleveland. Thome, a 13th-round pick in the 1989 draft, hit 334 home runs with the Indians.
"You never imagined when you sign, you'd get to this point," Thome said. "But it's really neat."