The pinch-hit homer tied the game for the Mets -- who went on to win, 5-4 -- and marked Sheffield's first off-the-bench knock since July 20, 1994, with the Marlins.
Sheffield's homer marks the first time in baseball history that a player's first home run with a team was also the 500th of his career.
He is also the first player to smack No. 500 as a pinch-hitter.
Just nine days after making his debut with the Mets, Sheffield was called on to pinch-hit after the Brewers replaced starter David Bush with the lefty Stetter.
"I wasn't thinking to pull the ball at all," Sheffield said when asked about the significance of his trademark dead-pull homer. "He was throwing me offspeed inside, and I kept hooking it, so I said, 'Just stay on the outside pitch.' And when it got 3-2, I was just thinking of getting on base and trying to win this game."
That mentality is the reason Sheffield's teammates erupted on the bench as if the veteran had played out his career in orange and blue.
"I was so excited when I looked over to the dugout," Sheffield said. "I was just thinking of those guys making it so relaxed for me to come here. And I appreciate every one of those guys. They've been very special to me."
Equally important to Sheffield was his reinforced belief that fate has its own plans.
After being released by the Tigers on March 31, the Mets took the chance and signed Sheffield just five days later.
"I knew there was a reason behind it," Sheffield said of not reaching 500 in Detroit. "There was a bigger reason and a higher purpose, and especially being released and coming back to New York [where he was a Yankee] and doing it. I knew there was a bigger reason, and I had to keep that in mind."
Also on Sheffield's mind was the irony of how the homer seemed to "wrap things up."
"It just relaxed me, just getting it out of the way," he said. "Doing it in front of our home fans. Doing it at the new stadium ... and the fact that it was [against] the first team I came in with, with Milwaukee. So it was big and special for me."
The fated ball traveled an estimated 385 feet into Citi Field's stands to christen Sheffield as the 25th player to reach 500 homers. Manny Ramirez was the last player to hit the mark, going deep on May 31, 2008, while with the Red Sox.
Sheffield (40 years, 143 days) became the fourth-oldest player to hit 500. Only (Ted Williams 41, 291), Eddie Murray (40, 194) and Willie McCovey (40 years, 171 days) were older.
Sheffield also joined an exclusive group with 500 homers, 2,500 hits, 1,500 RBIs and 200 stolen bases. Hank Aaron, Barry Bonds, Reggie Jackson, Willie Mays and Frank Robinson are the only other players in that lofty club.
While Sheffield was firm in his belief that passing idol and fellow Tampa, Fla., native Fred McGriff to hit No. 493 was the most special mark, he admits joining the 500 Club has its perks.
"Now I can say 'I'm in the club,'" Sheffield said. "And it's like your degree; no one can ever take that away from you."
After Friday night's curtain call, it's safe to say Sheffield isn't just in the 500 Club. He's in the Mets' club, too.