Boone attended Villa Park High School in Villa Park, California. He batted .423 with 22 stolen bases for the school’s baseball team in his senior year, and was named the Century League’s co-player of the year. The California Angels selected Boone on the third day of the 1991 MLB draft, but he had no intention to sign a professional contract. He attended the University of Southern California (USC) and played college baseball for the USC Trojans. In 1993, he played collegiate summer baseball for the Orleans Cardinals of the Cape Cod Baseball League, and Orleans won the league’s championship.

The Cincinnati Reds selected Boone in the third round of the 1994 MLB draft. Boone made his MLB debut in June 1997, and was ejected from the game after being called out sliding into home. On the last day of the 1998 season, the Reds started the only MLB infield composed of two sets of brothers: first baseman Stephen Larkin, second baseman Bret Boone, shortstop Barry Larkin, and third baseman Aaron Boone.

On September 22, 2002, Boone hit the last home run in Riverfront Stadium in the eighth inning, a solo home run off Dan Plesac. Boone hit a career-high 26 home runs in 2002, playing in all 162 games. The Reds named Boone their team’s most valuable player. He appeared in the 2003 MLB All-Star Game.

The New York Yankees acquired Boone from the Reds for Brandon Claussen, Charlie Manning and cash on July 31, 2003. In 54 games after the trade, he hit .254 with a .720 OPS, six home runs and 31 RBIs.

In January 2004, Boone tore the anterior cruciate ligament in his left knee during a pick-up basketball game. The game violated the standard MLB player contract, which forbids taking part in off-season basketball, skiing and surfing. The Yankees immediately hinted that they would terminate his contract. Soon after trading for Alex Rodriguez to play third base, the Yankees released Boone on February 27, 2004.

Boone signed a two-year contract with the Cleveland Indians in June 2004. He earned $600,000 for 2004, $3 million for the 2005 season, and a club option for the 2006 season worth $4.5 million. After missing the entire 2004 season, Boone played 154 games in 2005. He batted .243 with 16 home runs and 60 RBIs. The Indians exercised an option on Boone’s contract for the 2006 season. In his second season with Cleveland, he batted .251 with seven home runs.

On December 29, 2006, Boone signed a one-year contract with the Florida Marlins worth $925,000. He batted .286 in 69 games for the Marlins in 2007.

On December 6, 2007, Boone signed a one-year, $1,000,000 contract with the Washington Nationals.

On December 18, 2008, Boone signed a one-year $750,000, plus incentives, deal with the Houston Astros.

In March 2009, Boone underwent open-heart surgery to replace a bicuspid aortic valve, a condition that he has been aware of since childhood but which routine tests indicated had recently worsened. Boone stated that doctors told him he could play baseball when he recovers, but he was not sure if he would choose to do so. Boone returned to baseball on August 10, when he began his rehabilitation with the Corpus Christi Hooks, the Astros’ Double-A minor league affiliate. He played five innings and was hitless in two plate appearances. Boone stated after the game that his goal was to return to the major leagues by September 1, the date that major league rosters expand. Boone was activated on September 1, and added to the Astros’ expanded roster. On September 2, Boone made his season debut, playing at first base and going 0 for 3. On September 16, Boone stated that he was leaning towards retirement, and on October 4 he played his last game.

On February 23, 2010, Boone announced his retirement and that he would become an analyst for ESPN. Boone appeared on Monday Night Baseball and for Baseball Tonight’s pregame show on Sunday night. Boone called the 2014 and 2015 World Series for ESPN Radio with play-by-play announcer Dan Shulman. He and Jessica Mendoza became color commentators on Sunday Night Baseball with Shulman in 2016. Boone and Shulman continued to call World Series games for ESPN Radio through 2017.

After the 2017 season, the Yankees decided not to retain Joe Girardi as their manager. The Yankees hired Boone to succeed him on December 4, 2017. The Yankees started the 2018 season with a 6–1 win against the Toronto Blue Jays on March 29, 2018. On September 2, 2018, Boone was suspended for one game for making illegal contact with an umpire. He finished his first season with a 100–62 record, good for second in the American League East, and led the Yankees to the wild card game against the Oakland Athletics, despite losing star outfielder and team leader Aaron Judge for two months with a wrist injury. On October 3, 2018, the Yankees defeated the Athletics 7–2 to advance to the American League Division Series, giving Boone his first postseason win as a manager. The Boston Red Sox eliminated the New York Yankees three–games–to–one in the American League Division Series.

The Yankees started the 2019 season with a 7–2 win against the Baltimore Orioles on March 28, 2019. On September 19, after winning against the Los Angeles Angels 9–1, the Yankees clinched the American League East, becoming AL East Division Champions for the first time since 2012 and also earning their 100th win. Boone became the first manager in MLB history to have 100 or more wins in each of his first two seasons. The Yankees would go on to lose to the Houston Astros in the American League Championship Series.

Following the 2019 season, Boone was named a finalist for American League Manager of the Year award. He finished runner-up to Minnesota Twins manager, Rocco Baldelli.