He played in Major League Baseball (MLB) for the San Diego Padres, St. Louis Cardinals, Los Angeles Dodgers, and Milwaukee Brewers.

Gyorko won the 2010 Brooks Wallace Award as the best shortstop in the National Collegiate Athletic Association's Division I.

[9] Gyorko shifted to second base for his first year to accommodate senior Tyler Kuhn, who played shortstop.

[15] In 2009, he played collegiate summer baseball for the Brewster Whitecaps of the Cape Cod Baseball League (CCBL), where he was named a league all-star,[16][17][18][19] but he required shoulder surgery and was unable to play the entire summer season.

[20] After the season, he joined the United States national collegiate baseball team, but did not make the final roster.

[5] He was named to the CCBL All-Star Team,[21] and he competed in the home run derby, held at Fenway Park.

[8] Prior to Gyorko's junior season in 2010 he was named the preseason Big East Player of the Year[7] and a Third Team All-American by Baseball America.

[8] Continuing to play as a shortstop,[8] Gyorko batted .381 with 19 home runs and 57 RBIs in his junior year.

[35] Gyorko began the 2011 season with the Lake Elsinore Storm of the Class A-Advanced California League.

[36] Gyorko appeared in the California/Carolina League All-Star Game, and was named the Top Star as he batted 2-for-4 with a run scored and one RBI.

[30] In 576 at-bats for Lake Elsinore and San Antonio, Gyorko had 192 hits, 25 home runs, 114 RBIs, a batting average of .333 and a .400 on-base percentage (OBP).

[38] Gyorko began the 2012 season with San Antonio, where he batted .262 with six home runs and 17 RBIs in 34 games.

He was promoted to the Tucson Padres of the Triple-A Pacific Coast League (PCL) in mid-May, as the Padres promoted Everth Cabrera and Alexi Amarista from Tucson, released Orlando Hudson, and placed Jason Bartlett on the disabled list.

[6] He finished the season with a combined .311 batting average, .373 OBP, and .547 slugging percentage (SLG), with 30 home runs.

[6] Gyorko impressed Padres' manager Bud Black with his hitting ability and defense at second base.

[42] With injuries to infielders Chase Headley and Logan Forsythe, Gyorko made the Padres' Opening Day roster, with the opportunity to alternate between second and third base.

[50] Additionally, he became just the second rookie to lead the Padres in either category since Nate Colbert in San Diego's inaugural season in 1969.

[50] He was named to Baseball America's All-Rookie Team,[49] and finished sixth in NL Rookie of the Year balloting.

[b][53] Going into spring training in 2014, Gyorko began focusing on improving his plate discipline, while maintaining his aggressiveness in swinging at hittable pitches.

On April 14, Gyorko signed a five-year extension with the Padres worth $35 million, which was the third largest for a player with only one year of service in the majors.

[57] After struggling to start the season, with a .162 batting average, the Padres placed Gyorko on the 15-day disabled list on June 6 due to plantar fasciitis in his left foot.

With Matt Kemp and Justin Upton added to the Padres' lineup, Black hoped to reduce the pressure on Gyorko to perform.

[55] By late April, with Gyorko off to a 7-for-47 (.147) start to the season, he began to lose playing time to Yangervis Solarte,[61] and to Cory Spangenberg in May and June as he continued to struggle.

[62] On June 10, after hitting .210 with two home runs in 46 games, the Padres demoted Gyorko to the El Paso Chihuahuas of the PCL.

[71] Due to the emergence of Aledmys Díaz at shortstop and Wong's struggles, Gyorko received most of his playing time at second base.

[79] Despite two stints on the disabled list in 2018, Gyorko still appeared in 125 games, hitting .262 with 11 home runs and 47 RBIs.

[81] He played in 38 games for the Cardinals in 2019, batting .194 with two home runs and seven RBIs, before going on the injured list with a strained back.

[83] On July 31, 2019, the Cardinals traded Gyorko to the Los Angeles Dodgers along with international signing bonus space and cash considerations in exchange for Tony Cingrani and minor leaguer Jeffry Abreu.

[91] On April 12, 2021, Gyorko was announced as the manager of the West Virginia Black Bears for the inaugural season of the MLB Draft League.

He did not return to the franchise for the 2023 season and was replaced by fellow Morgantown native David Carpenter, ending his stint with the team with a 78–49–6 record.