The son of Connie and Mike Moustakas, a former college football player for UCLA, Mike was born in Los Angeles on September 11, 1988, and grew up in the Los Angeles area. He is of Greek descent, as his grandmother was born in Greece, and he flew a Greek flag above his locker in the Royals’ clubhouse. He is the nephew of author, MLB player and former New York Mets hitting coach Tom Robson, who gave Moustakas hitting tips growing up. Moustakas’ mother died in 2015 after a long illness.

Moustakas attempted to be a two-sport player for Chatsworth, but a broken ankle suffered in his first game as quarterback for the Chancellors ended his high school football career, and nearly ended his baseball career as well. However, after three months of rehabilitation Moustakas was able to resume playing baseball. In 2006 Moustakas was a member of USA Baseball’s Junior National Team, competing in the World Junior Championships in Cuba. He topped off his prep career by being named Baseball America ‘s High School Player of the Year in 2007, an honor previously bestowed on MLB stars like Joe Mauer, Homer Bailey and Josh Hamilton. Moustakas was also selected to the USA Today All-USA high school baseball team in 2007. He was offered a scholarship to USC, but turned it down and decided to enter the 2007 MLB draft.

The Kansas City Royals selected Moustakas with the second overall pick of the 2007 amateur draft. He signed with the team on August 15, 2007, receiving a reported signing bonus of $4 million. Chatsworth teammate Matt Dominguez was chosen by the Florida Marlins with the 12th overall pick of the amateur draft. The pair became just the sixth set of high school teammates to be selected in the first round of the same draft.

Entering 2009, Moustakas was widely regarded as one of the top baseball prospects in all of minor league baseball. The Sporting News ranked Moustakas as the 13th-best prospect overall, while MLB.com listed Moustakas as their 11th-best prospect in all of baseball. Moustakas, however, had trouble adjusting to the Carolina League in 2009. While his power remained, his ability to hit for a high average went down significantly. In 2010, Moustakas’ power and average increased significantly. As of July 13, 2010, Moustakas was hitting .352 with 21 homers and 76 runs batted in in AA Northwest Arkansas. On July 15, 2010, he was promoted to Triple-A Omaha. On August 30, 2010, Moustakas was named the 2010 Texas League Player of the Year and on the same night, he set an Omaha Royals record with three home runs and 11 RBIs in one game. Moustakas won the Joe Bauman Home Run Award for most home runs in minor league baseball, winning a tiebreaker with Mark Trumbo. On May 22, 2014, he was demoted to Triple-A Omaha after batting just .152 through 139 plate appearances.

Moustakas had his contract purchased by Kansas City on June 9, 2011. He made his debut the following night against the Los Angeles Angels of Anaheim, going 1–3 with a walk and a run scored. His first major league hit came in his third plate appearance against Ervin Santana, where he would eventually score in the 4–2 win. Moustakas went on to play in 89 games for Kansas City in 2011, finishing the season with five home runs, thirty RBIs, and a season batting average of .263.

On February 18, 2012 the Royals announced they had signed Moustakas to a one-year contract for the 2012 season. No financial terms of the deal were released. During the 2012 season Moustakas set a new club record for K.C., playing 47 straight games without an error. He also made 41 double plays far besting the previous mark of 34 Mark Teahen set in 2006. Moustakas finished the year batting .242 with a .296 OBP with 20 home runs and 73 RBIs, also hitting 34 doubles.

In 2013, he batted .233 with a .287 on base percentage, 12 home runs, and 42 RBI. He also led all American League third basemen with 16 errors.

Moustakas struggled early in the 2014 season. On May 22, 2014, he was demoted to Triple-A Omaha after batting just .152 through 139 plate appearances, though he led the team in homers with 4. On June 1, Moustakas was recalled from AAA. He began to hit more consistently after this. He finished the season batting .212, while hitting 15 homers and driving in 54 runs. Moustakas tore through the 2014 Playoffs, hitting 5 homeruns, including a go-ahead solo shot in the 11th inning of Game 1 against the Los Angeles Angels of Anaheim. He led all 2014 Postseason players in homers. The Royals would then lose to the San Francisco Giants in the 2014 World Series.

In 2015, Moustakas carried over his success from the postseason and had a batting average at or above .300 right up until the All-Star break. He was selected to the 2015 All-Star Game via the All-Star Game Final Vote. On May 15 against the Yankees, he went 4-for-5 with a homer shy for hitting for the cycle. Moustakas was placed on the family emergency list twice during the first half of the 2015 season. On September 12, Moustakas set a new Royals franchise record against the Baltimore Orioles, with 9 RBI, eclipsing the previous mark of seven set by Billy Butler and George Brett. He hit a grand slam, three-run home run and a two-run single in the 14-6 win. In 147 games, Moustakas batted .284 with 22 home runs and 82 RBI. The Royals won the World Series against the New York Mets to win the franchise’s first world championship in 30 years.

On May 7, 2016, Moustakas was placed on the 15-day disabled list due to a fractured left thumb. On May 22, Moustakas suffered a right knee injury while colliding with teammate Alex Gordon in an attempt to fetch a pop up in foul territory. The next day, an MRI revealed that there was a torn ACL in the knee, ending Moustakas’ 2016 season.

Moustakas won the All-Star Final Vote for the second time of his career on July 6, 2017, and participated in the Home Run Derby. On July 28, Moustakas hit his 30th home run of the season at Fenway Park, becoming the fastest Royal ever to reach the mark in a season. Moustakas had 38 home runs that season, a new Royals single season record.

On March 10, 2018, Moustakas re-signed with the Royals for one year and $5.5 million, plus a mutual option for 2019.

On July 28, 2018, Moustakas was traded to the Milwaukee Brewers in exchange for Brett Phillips and Jorge López. With the Brewers, he batted .256/.326/.441.

On October 4, 2018, Moustakas hit a walk-off single in the 10th inning of NLDS Game 1 vs the Colorado Rockies, giving the Brewers a 3-2 win and a 1-0 series lead. The Brewers later swept the series in three games, but would proceed to lose the NLCS to the Los Angeles Dodgers 4 games to 3. On October 30, 2018 Moustakas declined his half of a mutual option for 2019 and became a free agent.

On February 19, 2019, Moustakas re-signed with the Brewers, inking a one-year, $10 million deal with a mutual option for 2020. He declined his half of the option and became a free agent after the 2019 season.

On December 5, 2019, Moustakas signed a 4-year, $64 million contract with the Cincinnati Reds, the largest free agent deal in Reds history.