Ramirez led the Red Sox to World Series Championships in 2004 and 2007 before being traded to the Los Angeles Dodgers in 2008 as part of a three-team deal that also involved the Pittsburgh Pirates.

Though he played at various points in the Oakland Athletics, Texas Rangers, and Chicago Cubs systems, as well as internationally, Ramirez did not appear in another Major League game.

[10] With the Single-A Kinston Indians in 1992, Ramirez battled injuries but still hit .278 with 13 homers and 63 RBIs in 81 games and was named as the number three prospect and the "Most Exciting Player in the Carolina League" by Baseball America.

[10][11] In 1993, Ramirez was named "Minor League Player of the Year" by Baseball America while hitting .333 with 31 homers and 115 RBIs in 129 combined games with the Double-A Canton–Akron Indians and Triple-A Charlotte Knights.

[14] However, rather humorously, his first MLB hit off Perez was an automatic double that bounced into the left-field seats as left fielder Paul O'Neill pursued it.

[22] Because of his return, Roberto Alomar, Omar Vizquel, and Kenny Lofton all started getting better pitches to hit, which also significantly increased their batting averages.

[23] With free agency looming, Ramirez homered in his final game and at-bat in an Indians uniform, on October 1 against Toronto in front of the home fans at Jacobs Field.

The second-half surge of newly acquired fellow Dominican slugger David Ortiz gave the Red Sox a formidable one-two punch in the middle of the lineup with Ramirez.

In the decisive fifth game of their Division Series matchup against the Oakland Athletics, Ramirez broke a sixth inning 1-1 tie by launching a go-ahead three-run homer off Barry Zito that set up an ALCS showdown with the rival Yankees.

The very next inning, Yankees pitcher Roger Clemens threw a pitch high and inside to Ramirez, and Manny charged the mound, sparking the melee.

[30] During the offseason that followed, the new Red Sox ownership (led by John W. Henry) and management tried to rid themselves of Ramirez's massive contract, despite his high level of production.

However, all 29 other teams passed on the opportunity to claim Ramirez due to the high cost,[31] and Rodriguez was acquired by the Yankees instead, as a replacement for Boone after the latter had blown out his knee playing offseason basketball.

[33] Together they hit back-to-back home runs six times, tying the major league single-season mark set by the Detroit Tigers' Hank Greenberg and Rudy York and later matched by the Chicago White Sox's Frank Thomas and Magglio Ordóñez.

[33] In the 2004 Major League Baseball All-Star Game, Ramirez hit a two-run home run off Roger Clemens in the top of the first inning, giving his teammates a 3–0 lead.

[34] Ramirez, Derek Jeter (with a single), Ichiro Suzuki (with a double) and Iván Rodríguez (with a triple) became the first All-Star quartet that combined to hit for the cycle during the same inning.

He hit .385 in the 2004 ALDS, leading the Red Sox to a sweep over the Anaheim Angels, and setting up a rematch in the 2004 American League Championship Series against the Yankees.

[54] In the fourth inning of the series' final game, Ramirez combined with teammate David Ortiz to hit back-to-back home runs off pitcher Jered Weaver.

[55] The Red Sox advanced to the 2007 American League Championship Series against the Cleveland Indians where, on October 13, Ramirez hit his 23rd postseason home run, passing Williams for the most all-time.

[56] He helped the Red Sox to reach and win the 2007 World Series, where they swept the Colorado Rockies, by batting a combined .348 with four home runs and 16 RBI in the postseason.

On May 31, 2008, Ramirez hit his 500th home run, against Baltimore Orioles pitcher Chad Bradford at Camden Yards in the seventh inning on the first pitch.

[59] A heated altercation between Ramirez and teammate Kevin Youkilis took place on June 5, during a game at Fenway Park against the Tampa Bay Rays.

The altercation may have also been caused by Ramirez objecting to what he believed was excessive complaining by Youkilis about the strike zone, as well as the first baseman's penchant for sometimes throwing his helmet in frustration after making an out.

[60] Later in the season, during a series with the Houston Astros, Ramirez had a physical altercation with elderly Red Sox traveling secretary Jack McCormick.

[72] With Ramirez in the lineup, the Dodgers won the NL West, then swept the Chicago Cubs in the Division Series before losing in the NLCS to the eventual World Series-winning Philadelphia Phillies in five games.

After long and contentious negotiations that dragged into the start of spring training, Ramirez signed a two-year $45 million contract to remain with the Dodgers on March 4.

[91] As a pinch hitter, he was ejected on August 29 by home plate umpire Gary Cederstrom one pitch into his at-bat for arguing a strike call.

He became a free agent at the conclusion of the season, which ended with the White Sox finishing 88-74, six games out of first place in the AL Central, and missing the postseason.

[101] Upon hearing that his plans to play in the winter league would not work, Ramirez decided that he was willing to serve his 100-game suspension for the second violation of the drug policy, and to request reinstatement with MLB.

"[102] On December 4, it was announced that Ramirez had formally filed papers with the league to be reinstated to baseball and that an agreement had been reached between MLB and the Players Association that he needed to serve only a 50-game suspension instead of 100 games.

[135] As of July 2024, both the younger Manny and Lucas are outfielders for the Victoria Harbourcats, a summer collegiate baseball team in the West Coast League.