He was named as one of the top five prep baseball players in the country by several scouting agencies by the time he graduated in 2008, including number two by Rivals.com and third by both RISE Magazine and Sports Illustrated. As “one of high school baseball top power hitters” by scouts, and a consensus top 10 pick, Hosmer was chosen by the Kansas City Royals in the first round (third overall selection) of the 2008 MLB draft. Hosmer remained unsigned for most of the summer while the Royals general manager Dayton Moore and Boras, operating as Hosmer’s agent, negotiated a deal. During negotiations, Hosmer helped lead his team based in Cincinnati, to a second-place finish at the American Amateur Baseball Congress Connie Mack World Series. Both sides agreed to a contract ten minutes before the signing deadline for drafted players on August 15, 2008. He received a $6 million signing bonus, the largest sum given to a draft pick in Royals history.

In Hosmer’s first full season in the minor leagues, he was assigned to the Burlington Bees in the Class A Midwest League. At Burlington, Hosmer struggled at the plate. By June 1, he had hit only one home run in 31 games while leading the team in strikeouts. He missed some time with a left pinkie finger injury. At the end of the season, Hosmer hit .241 with six home runs. He later mentioned the 2009 season as “a tough year”. In 2010, Hosmer was named the seventh best first base prospect by Scout.com. He started the season with the Royals’ Class A-Advanced affiliate, the Wilmington Blue Rocks of the Carolina League. where his struggles continued. He was soon diagnosed with astigmatism, an eye condition and had laser surgery to correct the problem. Hosmer returned to the Blue Rocks a week later and his hitting significantly improved. By May 23 he was hitting .388 with a .571 slugging percentage. He played in the 2010 All-Star Futures Game where he had four hits and two RBI in a 9-1 victory. For his effort, Hosmer was promoted to the Northwest Arkansas Naturals of the Class AA Texas League on July 17, where in his first at-bat he hit a home run. During the playoffs Hosmer hit six home runs, which was individually, the second highest total in a single Texas League playoff series. The team went on to win the Texas League championship.

The Royals’ farm system was ranked number one in baseball entering the 2011 season, led by Hosmer and another top prospect, third baseman Mike Moustakas. Most baseball critics agreed that the Royals, a team that was known for mediocrity the past two decades, would be a contender within a couple of years, and they had nine prospects in Baseball America’s top 100, a record for the publication. Hosmer was ranked as the best first baseman prospect in Major League Baseball prior to the 2011 season. He was also rated the eighth best overall prospect by Baseball America, and the top Royals prospect overall. So much hype was placed on the Royals that general manager Dayton Moore traded the team’s best player, Cy Young Award winner Zack Greinke to the Milwaukee Brewers for four top prospects, to focus on the team’s future. Hosmer began the season with the Royals Class AAA affiliate, the Omaha Storm Chasers of the Pacific Coast League (PCL). When the Royals purchased Hosmer’s contract on May 5, 2011, he was leading the minor leagues with a .439 batting average and the PCL with 43 hits and a .525 on-base percentage.

The Royals recalled Hosmer on May 5, 2011. Veteran catcher Jason Kendall was moved to the 60-day disabled list to make space for Hosmer on the 40-man roster. He made his MLB debut at first base the following day against Oakland Athletics starter Gio González, replacing Kila Ka’aihue. Prior to his debut, Hosmer was being touted by journalists as a “super-prospect” and the “most-hyped” rookie to debut for the Royals since Bo Jackson. The Royals promoted Hosmer before a mid-June deadline in which the Royals could have avoided salary arbitration for an extra year. Hosmer went hitless in two at-bats, striking out twice. He also walked twice and stole a base in a 3–2 loss as the Royals had the second biggest crowd of the season.

On February 18, 2012, the Royals announced they had signed Hosmer to a one-year contract for the 2012 season. No financial terms of the deal were released. During spring training, Hosmer led all players with 29 RBIs and had a slugging percentage of .714. Discussing Hosmer’s spring training, Royals Hall of Famer George Brett said, “He’s a baseball player… He acts like a baseball player. And boy, he’s going to be a damn good one, too.” By opening day, the Kansas City media was hyping Hosmer as the “face of the franchise”, the city’s ” next future sports star”, among other commentary after his performance last year. He started at first base on opening day against the L.A. Angels, going 0-for-4. He hit a home run in a 6-3 victory the next day but later struggled, hitting below .200 for the first couple of weeks of the season as the Royals endured an 11-game losing streak entering April 24. He ended the season with a .232/.304/.359 slash line to go along with 14 home runs and 60 RBIs.

In 2013, Hosmer’s defense earned him his first Gold Glove Award. He finished the year with a .302 batting average, 17 home runs, and 79 RBI.

On July 20, 2014, in a game against the Boston Red Sox, Hosmer was hit in the hand by a pitch from Jon Lester. At first, he was only day-to-day with a bruised hand. However, on July 31, in a game against the Minnesota Twins, he aggravated the injury on a checked swing in the fourth inning. X-rays revealed a displaced fracture of the third finger on his right hand. Hosmer missed four weeks due to the injury. He finished the season batting .270, 9 home runs and 58 runs batted in.

In the 2014 postseason, Hosmer helped lead the Royals to a record-setting run, winning three consecutive extra-inning games. After getting on base five times in the wildcard game against the Oakland A’s, Hosmer also slammed a game-winning, two-run homer in Game 2 of the ALDS against the Los Angeles Angels of Anaheim. In doing so, the first baseman became the first player in MLB history to hit both a triple and a home run during extra innings in one year’s postseason.

On February 18, 2015, Hosmer and the Royals agreed to a $13.9 million, two-year contract. He would earn $5.65 million during the 2015 season and $8.25 million during the 2016 season, and would be eligible for arbitration again in 2017. He would not be eligible for free agency until the 2017 Off season. During the 2015 season, Hosmer had a career year with a .297 batting average, with 18 home runs and 93 RBIs. Hosmer also recorded the final putout of the AL Central and the American League Championship Series clinching games. On October 23, Hosmer tied George Brett for the most RBIs in the postseason (23) in Royals’ franchise history when he singled Lorenzo Cain home from first base representing the go-ahead run in Game 6 of the ALCS. In Game 1 of the 2015 World Series, Hosmer overtook Brett’s record for the most RBIs in the postseason with a walk-off sacrifice fly to bring in Alcides Escobar in the 14th inning, representing Hosmer’s 25th postseason RBI and helping atone for an eighth-inning error that helped the Mets take a one-run lead. Hosmer starred again in game 2 with two hits, a run scored, and two RBIs to help the Royals take a 7-1 win and a 2-0 series lead. On November 1, 2015 Hosmer scored the tying run in the 9th inning which eventually led to the Royals win in game 5 of the World Series

Hosmer won his third consecutive Gold Glove Award in 2015.

On July 12, 2016, Hosmer was named the 2016 MLB All-Star Game MVP in San Diego. In the second inning of the All-Star Game, he hit a game-tying home run off of former teammate, Johnny Cueto. In 158 games of 2016, Hosmer finished with a .266 batting average, a career-high 25 home runs, and 104 RBI.

In 2017, Hosmer played all 162 regular season games and finished with a career-high .318 batting average while tying his best of 25 home runs. He added 94 RBI along with a career-best .385 on-base percentage. After the season, Hosmer became a free agent for the first time of his career. He won his fourth career Gold Glove Award.

Hosmer played for Team USA in the 2017 World Baseball Classic. He hit the go-ahead home run in a second-round comeback win over the team from Venezuela. Following the conclusion of the tournament, he was named to the 2017 All-World Baseball Classic team.

On February 19, 2018, Hosmer signed an eight-year, $144 million contract with the San Diego Padres, the largest contract in Padres franchise history at the time. Hosmer changed his jersey to No. 30 in honor of former Royals teammate Yordano Ventura, who had died a year earlier. Hosmer’s previous No. 35 was already retired by the Padres for Randy Jones. In his first season as a Padre, Hosmer hit .253 with 18 home runs and 69 RBIs.

On August 20, 2020, Hosmer hit a grand slam against the Texas Rangers, making the Padres the first team in MLB history to hit a grand slam in four consecutive games, following grand slams by Fernando Tatis Jr., Wil Myers and Manny Machado.