The Los Angeles Dodgers selected Goldschmidt in the 49th round of the 2006 MLB draft. The Dodgers knew he was a long shot to sign with them, but selected him nonetheless. Goldschmidt played with the son of one of the Dodgers’ scouts. He enrolled at Texas State University to play college baseball for the Texas State Bobcats baseball team. He was named the Southland Conference hitter of the year in 2008 and 2009, Southland player of the year in 2009, and was a third-team All-American as a junior in 2009 after hitting .352 with 18 home runs and 88 runs batted in (RBIs) in 57 games played. Goldschmidt set Bobcat career records with 36 home runs and 179 RBIs.

Goldschmidt met his wife, Amy (née Glazier), during his freshman year at Texas State; they married in October 2010. The couple have two children, a son and a daughter. Goldschmidt became an evangelical Christian as an adult; he has Jewish and German ancestry. In September 2013, Goldschmidt graduated from the University of Phoenix with a Bachelor of Science degree in management.

In 2011, Goldschmidt played for the Mobile Bay Bears of the Class AA Southern League. He had a .306 batting average, 30 home runs, and 94 RBIs in 103 games played through the end of July, leading all minor leaguers in home runs and RBIs, while his 82 walks was third-best. After the season, Goldschmidt was again named the Diamondbacks’ player of the year, a Baseball America first-team Minor League All-Star, Class AA all-star first baseman, Southern League all-star first baseman, and the Southern League’s Most Valuable Player.

The Diamondbacks promoted Goldschmidt to the MLB on August 1, 2011. The Diamondbacks intended to platoon Goldschmidt with Xavier Nady. Goldschmidt recorded a base hit in his first MLB at-bat on August 1, and hit his first MLB home run the next day off San Francisco Giants pitcher Tim Lincecum. After Nady broke his wrist in mid-August, the Diamondbacks signed Lyle Overbay to replace him. Goldschmidt has credited Overbay for his mentorship. Goldschmidt struck out 20 times in his first 44 MLB at bats. In his rookie season, Goldschmidt batted .250 with eight home runs and 26 RBIs in 48 games.

The Diamondbacks made the postseason, and played against the Milwaukee Brewers in the 2011 National League Division Series (NLDS). In Game 3, Goldschmidt hit a grand slam to extend the team’s lead in its first victory of the series. His home run was the third grand slam by a rookie in MLB postseason history. The Diamondbacks lost the series in five games, and Goldschmidt batted .438 with six RBIs and an OBP of .526.

Goldschmidt and Overbay made the Diamondbacks’ Opening Day roster in 2012. Goldschmidt hit his first career regular-season grand slam on June 1, 2012, off of Chicago Cubs pitcher Carlos Mármol at Wrigley Field. Four days later, Goldschmidt hit another grand slam off St. Louis Cardinals reliever Maikel Cleto. Overbay played sparingly, and was designated for assignment at the end of July. In 2012, Goldschmidt played 145 games and batted .286 with 20 home runs, 82 runs, 82 RBIs, 43 doubles, and 18 stolen bases.

Before the 2013 season, the Diamondbacks and Goldschmidt agreed to a $32 million contract covering the 2014 through 2018 seasons with a club option for the 2019 season worth $14.5 million. He would not have been eligible for salary arbitration until the 2014–15 offseason and free agency until the 2017–18 offseason. Goldschmidt was selected to the National League’s team in the 2013 Major League Baseball All-Star Game. Goldschmidt doubled with two outs in the ninth inning, one of only three hits for the National League, and the only extra-base hit. On August 13, he hit a game-tying home run against the Baltimore Orioles in the bottom of the ninth inning to send the game into extra innings. Goldschmidt then hit a walk-off home run in the bottom of the eleventh. Goldschmidt hit a third grand slam on August 20, 2013, against J. J. Hoover of the Cincinnati Reds. In 160 games that season, he attained a .302 batting average, 36 home runs, and 125 RBIs. Goldschmidt finished second in the voting for the National League’s Most Valuable Player Award, behind Pittsburgh Pirates outfielder Andrew McCutchen. He led MLB with four walk-off hits in 2013.

Goldschmidt was the starting first baseman for the National League in the 2014 MLB All-Star Game. In 2014, Goldschmidt batted .300 with 19 home runs, 75 runs, and 69 RBIs. His season ended on August 1 when Pittsburgh Pirates pitcher Ernesto Frieri hit him in his hand with a pitch, breaking a bone. He spent the rest of the year on the disabled list.

On June 10, 2015, Goldschmidt hit his 100th career home run against Brett Anderson of the Los Angeles Dodgers. At the time of his 100th home run, Goldschmidt was sixth on the Diamondbacks’ all-time home run list. Later that year, Goldschmidt was again the starting first baseman for the National League in the All-Star Game. Goldschmidt attained a .321 batting average with 33 home runs and 110 RBIs, with a major-league leading 29 intentional walks, in 2015. He also was 2nd in the league in power-speed number (25.7). He won his second Gold Glove Award and Silver Slugger Award. For the second time in three seasons, Goldschmidt was voted the runner-up for the National League Most Valuable Player Award, this time finishing behind Washington Nationals outfielder Bryce Harper.

In 2016, Goldschmidt batted .297 with 24 home runs, 106 runs, and 95 RBIs in 579 at-bats. He also was third in the league in power–speed number (27.4). He was selected to appear in the 2016 MLB All-Star Game, where he went 0-for-3.

On August 3, 2017, Goldschmidt hit three home runs in a game for the first time, bolstering the Diamondbacks’ 10–8 win over the Chicago Cubs. For the fifth time in his career, Goldschmidt was named to the National League’s All-Star Team. On September 13, 2017, in a game against the Colorado Rockies, Goldschmidt recorded his 1,000th career hit. Goldschmidt finished the 2017 season batting .297 with 36 home runs, 117 runs, and 120 RBIs. He tied for the National League lead in power-speed number (24.0). After the season, Goldschmidt was awarded his third Gold Glove Award and Silver Slugger Award. He also finished third in voting for the National League Most Valuable Player Award.

In the 2017 National League Wild Card Game, Goldschmidt hit a three-run home run in the first inning that helped the Diamondbacks to win 11–8 over the Rockies. During the 2017 NLDS, Goldschmidt batted only .091. The Diamondbacks lost the series to the Los Angeles Dodgers.

Through the first 20 games in May of the 2018 season, Goldschmidt struggled, managing to get only seven hits out of 73 at-bats (.096). At the time, this lowered his batting average for the season to just .198. Goldschmidt improved in the following month, recording a .390 batting average between the dates of June 1 and July 3. For the month of June, he won the National League Player of the Month Award for the first time in his career. His efforts earned him a spot on the All-Star Team for a sixth consecutive year. On August 3, 2018, Goldschmidt hit his 200th career home run against Chris Stratton of the San Francisco Giants. Goldschmidt finished the 2018 season batting .290 with 33 home runs, 95 runs, and 83 RBIs. His 1,088 games played, 209 home runs, 710 RBIs, 1,179 hits, 708 runs scored, and 267 doubles are second in Diamondbacks’ history, behind Luis Gonzalez. After the season, the Diamondbacks exercised the $14.5 million option on Goldschmidt’s contract for the 2019 season.

On December 5, 2018, the Diamondbacks traded Goldschmidt to the St. Louis Cardinals in exchange for Luke Weaver, Carson Kelly, Andy Young, and a Competitive Balance Round B pick in the 2019 MLB draft.

On March 23, 2019, Goldschmidt and the Cardinals agreed to a five-year contract extension worth $130 million, spanning the 2020–24 seasons. The deal became the largest in team history, eclipsing the seven-year, $120 million contract with Matt Holliday signed in 2010. In his second game with the Cardinals against the Milwaukee Brewers, he hit three home runs and became the first player in Major League history to hit three homers in either his first or second game with a new team.

On April 20, 2019, in a game against the New York Mets Goldschmidt hit a 465-foot home run off Paul Sewald that would become both his longest career home run and the longest home run hit at Busch Stadium during the Statcast era. On June 21, 2019, in a game against the Los Angeles Angels, Goldschmidt hit a foul ball that ended up flying over the upper deck seating and out of the stadium, the first such occurrence in the current Busch Stadium. On July 26, 2019, in a game against the Houston Astros, Goldschmidt reached a streak of six home runs in six consecutive games for the first time in his career, also tying the Cardinals franchise record previously set by Matt Carpenter and Mark McGwire. Goldschmidt finished his 2019 regular season, and his first season as a Cardinal, slashing .260/.346/.476 with 34 home runs and 97 RBIs over 161 games. On defense, he had the best fielding percentage of all major league first basemen (.996). Following the season, he was nominated for his first ever Gold Glove in a Cardinals uniform.

In 2020, Goldschmidt appeared in 58 games batting .304/.417/.466 with six home runs and 21 RBIs in 231 at bats. On October 28, 2020 he underwent surgery to have a bone spur removed out of his right elbow.