The New York Yankees star wasted no time, connecting in the first inning on a first-pitch, 95 mph fastball from Detroit ace Justin Verlander.
Out of baseball last year while serving a drug suspension, Rodriguez became the 29th player in major league history to reach 3,000 hits. He was the first to do it since Yankees great Derek Jeter homered from the very same batter's box in 2011.
"It's a magical number," Rodriguez said after the final out of New York's 7-2 victory. "I'm very happy to be in the club."
With the crowd at Yankee Stadium standing in anticipation, Rodriguez sent a high drive to right field. He held onto the bat as he took a few steps toward first base, and outfielder J.D. Martinez bumped into the wall as he backed up.
Fans roared as the ball sailed a half-dozen rows into the seats.
Rodriguez pointed to the crowd a couple of times and blew a kiss to someone behind the backstop after crossing the plate. He was greeted by Mark Teixeira and other teammates between the plate and the dugout, and got a big hug from manager Joe Girardi.
The only other players to hit a homer for No. 3,000 were Jeter and Wade Boggs.
Retrieving the souvenir ball might be harder for Rodriguez than hitting it. Zack Hample, a 37-year-old who describes himself as a professional home run ball catcher, wound up with the prized keepsake.
Hample originally told the Yankees he had no intention of giving it back. He watched the ninth inning with team president Randy Levine and chief operating officer Lonn Trost, and said he's considering what to do.
"Now, I'm thinking about it," he told The Associated Press in a telephone interview.
"There's no right thing to do," he said. "I want to enjoy the moment."
A day earlier, Hample tweeted that Rodriguez "deserves favours from no one, least of all a fan."
Rodriguez turns 40 next month. The three-time AL MVP launched his 13th homer of the season and has enjoyed a productive year as a designated hitter after returning from his suspension.
Rodriguez hit his 667th career home run after beginning the day with a .299 lifetime average in 21 seasons. He joined Hank Aaron and Willie Mays as the only players with 600 homers and 3,000 hits.
Earlier this year, Rodriguez passed Mays for fourth place on the all-time homer list and eclipsed Barry Bonds for second on the official RBIs chart.
"I'm enjoying this season as much as any," he said.
Unlike with home run No. 660 that tied Mays, there was no marketing agreement between Rodriguez and the Yankees regarding this milestone — and thus, no potential squabble over $6 million. The team even tweeted updates throughout his pursuit, using the hashtag AROD3K.
This hit was quite different from his first one — a four-hop, infield single on July 9, 1994, at Fenway Park against Boston's Sergio Valdez. Back then, Rodriguez was an 18-year-old batting last for the Seattle Mariners, a young man with a big future.
Friday night's plate umpire, Ed Hickox, coincidentally was behind the plate for A-Rod's first hit, too.
"Is that right — 21 years apart?" Hickox said an hour before the first pitch. "I was aware he was a prospect for Seattle when he got the hit, but that's all we knew then."
For all his achievements, A-Rod has been a polarizing lightning rod in recent years. While the crowd in the Bronx cheered him, there are many fans who will forever attach an asterisk to anything Rodriguez accomplishes.
Such is the baseball world in the wake of performance-enhancing drugs, where RBIs, ERAs and other huge numbers have been tainted by PEDs. Bonds, Roger Clemens and Mark McGwire are among the many with Cooperstown-caliber credentials who haven't come close to being elected to the Hall of Fame because of drug scandals.
High school student Claire Campo, from Mission Viejo, California, bought a $135 Rodriguez jersey in the souvenir store an hour before the game.
"I love Alex Rodriguez," she said. "People need to get off his case. He's done everything you could ask for on the field. What he's done off the field, he apologized and paid the price. What more do you want?"
Her grandfather, Larry Vastola of Morristown, New Jersey, said he completely agreed with her. But he said his wife — Campo's grandmother — had a different view.
"She can't stand him," he said. "When we get home, we're going to tell her that they dislike him so much at Yankee Stadium that they were giving away these jerseys."
Rodriguez was the No. 1 pick in the 1993 draft. He became a star in Seattle, later joined Texas and was traded to the Yankees after the 2003 season. His 3,000th hit was his 1,465th with the Yankees.
As Rodriguez ascended to becoming a perennial All-Star, many looked at him as a player who could help restore credibility to the record books while stars such as Manny Ramirez, Sammy Sosa and Rafael Palmeiro were caught up in drug scandals during the late 1990s and 2000s.
But in 2009, Rodriguez admitted to using steroids while with Texas. His involvement in the Biogenesis drug investigation near Miami, where he lives in the off-season, was a low point and it got him suspended for a year after an acrimonious appeal.
After suing MLB and the Yankees — all lawsuits have been dropped — Rodriguez returned to baseball with trepidation. But he has won back some fans in New York by being a productive player on the field and a model citizen off the diamond.
Rodriguez homered on the birthday of late Yankees hero Lou Gehrig, and connected a day before Yogi Berra, Whitey Ford, Reggie Jackson, Boggs and other New York stars return for Old-Timers' Day.
Jeter finished with 3,465 hits. His milestone day was indeed monumental, when he went 5 for 5 with the deciding hit. The buzz leading up to his 3,000th became the talk of baseball and when he homered off Tampa Bay's David Price — now with the Tigers — the crowd responded with a 4-minute ovation.
As Jeter rounded the bases, first baseman Casey Kotchman doffed his hat and several Tampa Bay players came out of the dugout to applaud.
Rodriguez came out for a curtain call after his homer, but there was nothing close to the outpouring of love that Jeter received. Cleveland Cavaliers star Kevin Love and New York Knicks executive Phil Jackson were among those in attendance.
Rodriguez homered off Verlander for the fourth straight game, and popped up and grounded out in his next two at-bats. A-Rod has tagged a lot of pitchers over the years, getting 26 hits off knuckleballer Tim Wakefield and 25 off David Wells.
The pitcher who has held Rodriguez hitless the longest? Arizona lefty Oliver Perez, against whom Rodriguez is 0 for 11.
Rodriguez tied the late Roberto Clemente with 3,000 hits, and can rapidly move up the list. Craig Biggio is 21st and reachable this year with 3,060, and Cal Ripken is 15th at 3,184.
Pete Rose owns the career record with 4,256. As for who will next reach 3,000, it's hard to say.
Ichiro Suzuki, now a part-time player for the Marlins, is closest to Rodriguez and began the day with 2,886 hits. Adrian Beltre followed with 2,657 and Albert Pujols had 2,585. Tigers star Miguel Cabrera had 2,266 and is 32.
Before Jeter, no player had gotten his 3,000th hit in a Yankees uniform. Now, the last two to accomplish the feat did so wearing pinstripes.
AP Baseball Writers Howie Rumberg and Mike Fitzpatrick contributed to this report.