After a brief call-up in 2006, when he hit just .191 in 89 at-bats, Pedroia became the regular second baseman for the Red Sox in 2007 replacing Mark Loretta. Pedroia suffered through an early-season hitting slump, but recovered, later putting up a 13-game hitting streak and a five-hit game against the Giants. He notably made a diving stop to preserve fellow rookie Clay Buchholz’s no-hitter on September 1. Pedroia won the AL Rookie of the Year award and was selected to the 2007 Topps Major League Rookie All-Star Team.

The Red Sox played the Indians in the 2007 ALCS. In Game 7 of the series, Pedroia homered and doubled, collecting five RBI to secure the Red Sox’ spot in the World Series, to face the Rockies. Pedroia homered in the first at bat of the series, making him only the second player, and the first rookie, to lead off the Series with a home run. The Red Sox went on to win their second World Series title in four seasons – and the first World Series championship for Pedroia.

On December 3, 2008, Pedroia signed a six-year contract extension worth $40.5 million, with an additional team option for 2015 worth $11 million.

Pedroia announced on December 15, 2008 that he would play for the United States team in the 2009 World Baseball Classic. He recorded the first Major League hit in Citi Field history during an April 3 exhibition game against the Mets. He hit a home run in his first at bat of the 2009 season.

Pedroia achieved his first multi-home run game on September 9, 2009, against the Orioles.

On January 9, 2009, Pedroia was named as the cover athlete of the baseball video game MLB 09: The Show, and appeared in several commercials for the game.

In August 2009, Pedroia’s wife, Kelli, gave birth to the couple’s first child, a boy named Dylan. In September 2012, Pedroia’s wife Kelli had a second son, Cole. On June 2014, the couple had their third son, Brooks. Pedroia is the nephew of Carolina Panthers defensive coordinator Phil Snow.

In a 2009 interview given to Boston magazine, Pedroia criticized his home town of Woodland, California, calling it a “dump” and a city that never embraced him. This generated backlash from his hometown and his family received death threats. Pedroia later clarified his comments saying he was only joking and his comments were taken out of context. The original article’s author, however, insisted that his use of the comment was not misleading. His transcript of the interview quoted Pedroia as saying “It’s a dump. You can quote me on that. I don’t give a shit.”

In 2010, MLB umpire Joe West made controversial statements regarding the speed of play between the Red Sox and Yankees, Pedroia responded by saying, “What he doesn’t understand is that when we don’t do well in these games against the Yankees, we get killed. If he doesn’t want to do Red Sox and Yankee games, he should tell the umpires’ union. Then when we’re in the World Series, he’ll be out of that assignment, too.”

On June 24, 2010, Pedroia went 5 for 5, with 5 RBI, and hit three home runs in a game against the Rockies that the Red Sox won, 13–11, in the tenth inning. The next day, Pedroia fouled a ball off his foot in an at-bat versus the Giants. MRI results the next day confirmed that he had a broken bone in his foot, and he was placed on the 15-day disabled list. Pedroia was under doctor’s orders not to put weight on his injured foot for two weeks, but continued to practice fielding grounders while on his knees.

Pedroia was named to be a reserve player on the 2010 AL All Star team, but did not participate due to this injury, and had former Arizona State teammate Ian Kinsler replace him on the roster. Pedroia returned to the lineup on August 17 against the Angels, only to be put back on the DL after playing 2 games. Pedroia would end the 2010 season having played only 75 games.

In 2011, Pedroia bounced back, batting .307 and slugging 21 home runs over 159 games. He won a Fielding Bible Award in 2011 as the best fielding second baseman in MLB, and had his best defensive season by ultimate zone rating, with 18.1 runs saved. In June and July, Pedroia had a 25-game hitting streak, the longest for a Red Sox second baseman. On August 16, Pedroia was involved in throwing a triple play, started by Jed Lowrie. Pedroia’s 2011 season was rated at 7.6 Wins Above Replacement by Fangraphs, an “MVP-caliber” performance.

On September 30, 2012, Pedroia broke his left ring finger but, after being reassured the injury would not degrade with use, he made the decision to play through the pain in the following season-ending series at Yankee Stadium.

On July 23, 2013, Pedroia and the Red Sox agreed to an 8-year extension worth $110 million. Pedroia was represented in negotiations by Sam Levinson and Seth Levinson of ACES Inc.

In November 2013, Pedroia underwent thumb surgery to repair a torn UCL, an injury he suffered when sliding to first base on opening day.

In May 2014, Pedroia hit his 100th career home run and his 300th career double. Pedroia hit only four home runs before the 2014 All Star break, and his hitting productivity dropped to league average. For the season he batted .278/.337/.376. However, his fielding numbers remained strong. For his defensive performance, Pedroia was honored with the American League Gold Glove award at second base—his fourth in his nine-year career—along with his third Fielding Bible Award. This made him the first Red Sox infielder to win four Gold Gloves.

Pedroia began the 2015 MLB season with two home runs in the Red Sox opening game, on the road at Citizens Bank Park, Philadelphia. On June 25, 2015 the Red Sox placed him on the 15-day disabled list due to a right hamstring strain.

The Red Sox finished the 2016 season with a 93-69 record, clinching the AL East division, but were swept in three games by the Indians in the 2016 ALDS. On October 13, Pedroia underwent left knee surgery, a partial medial meniscectomy and chondroplasty. He won a 2016 Fielding Bible award. He also won the 2016 Wilson Defensive Player of the Year Award for second base, in all of MLB.

Pedroia has garnered multiple nicknames during his time in Boston, including Pedey, the Laser Show, and the Muddy Chicken. His family is of Swiss Italian and Portuguese heritage. The Red Sox officially lists Pedroia at 5 feet 9 inches (1.75 m), but he said he is 5 feet 7 inches (1.70 m) in 2016. Pedroia has expressed an interest in Bigfoot, including tweeting about the show Finding Bigfoot from his Twitter account. Pedroia enjoys playing the game cribbage; he and former manager Terry Francona used to play together. Pedroia is a fan of the NBA’s Sacramento Kings, and the NFL’s San Francisco 49ers.

On March 7, 2019, Pedroia made his spring training debut, hitting a single in his lone at bat of the game while playing in the field for two innings; it was his first game action since May 2018. He began the season on the injured list. On April 4, he was sent to the Class A Greenville Drive on a rehabilitation assignment, where he played in three games, batting 3-for-9. Pedroia was activated for Boston’s home opener on April 9, appeared in six games while batting 2-for-20 (.100/.143/.100), and returned to the injured list on April 18 due to left knee irritation. He began a rehabilitation assignment with Double-A Portland on May 2. On May 11, he was scratched from a start due to knee discomfort, and his assignment with Portland was halted on May 13. He restarted his rehabilitation, first with Triple-A Pawtucket on May 17, and then with Double-A Portland on May 24. Pedroia was removed from Portland’s May 25 game due to left knee soreness.

After being evaluated, he announced on May 27 that he was going to take some time to evaluate his future. When asked if he would ever play again, he said “I’m not sure.” The same day, the Red Sox moved Pedroia to the 60-day IL. On August 6, Pedroia underwent a left knee joint preservation surgery. In 2019, he had the slowest sprint speed of all American League second basemen, at 25.0 feet/second.

On January 21, 2020, it was reported that Pedroia suffered a “significant setback” with his left knee. On February 23, the team placed Pedroia on the 60-day injured list. Due to his injury, Pedroia missed the entirety of the shortened 2020 season.