He played in Major League Baseball (MLB) for the Minnesota Twins, Chicago White Sox, Pittsburgh Pirates, Toronto Blue Jays, Houston Astros, and Detroit Tigers.

After the 2003 season, the Giants traded him to the Minnesota Twins, along with pitchers Joe Nathan and Boof Bonser, in exchange for catcher A. J.

[2] Often compared to former teammate Johan Santana, another hard-throwing lefty, Liriano was touted as one of the "super-prospects" within the Twins organization.

[citation needed] As a member of the Rochester Red Wings, Minnesota's Triple-A farm club, Liriano was awarded the 2005 International League Rookie of the Year.

[5] Liriano began the 2006 season in Minnesota's bullpen, but was promoted to the starting rotation in May, exchanging positions with struggling starter Carlos Silva.

[6] He started the season 12–3 and won the American League Rookie of the Month awards for June and July.

[7][8] He was named by American League manager Ozzie Guillén as one of five candidates for the 2006 All-Star Final Vote and finished second to the player he was traded for, A. J. Pierzynski.

Guillén selected Liriano for his first All-Star game to replace fatigued starting pitcher José Contreras.

He made a rehab start for Triple-A Rochester on September 9, throwing 40 pitches for four strikeouts and one walk in three hitless innings.

[13] On November 6, 2006, Liriano underwent Tommy John surgery to curtail the pain in his left elbow.

[16] On April 25, Liriano was sent back to the minors after a rough start to the season coming off Tommy John surgery.

[17] After recording an ERA of 2.67 and going 10–0 in his 11 most recent minor league starts, the Twins recalled Liriano on August 1, from Triple-A Rochester Red Wings, replacing Liván Hernández in the rotation.

[21] Between those strong flashes of brilliance though, he logged several sub-par showings, frequently giving up several runs during short times on the mound.

He helped his club earn a postseason berth and then went 3–1 with a 0.49 ERA in seven playoff starts, while recording 47 strikeouts and five walks in 37 innings, as Leones del Escogido won the league championship.

Liriano reported to spring training lighter than usual, and Twins coaches expressed guarded optimism that he had regained some of his 2006 form.

Over an eleven start stretch from July 16 (his first game after the All-Star break) to September 14, Liriano posted an 8–0 record to go along with a 2.41 ERA.

Across this span, he limited hitters to a .227 batting average, struck out 72 in 71 innings against 25 walks, and gave up only two home runs.

Despite his ERA only ranking 14th in the league, Liriano posted an extremely low FIP primarily due to his ability to limit home runs.

On May 3, Liriano pitched his first career complete game, a 1–0 no-hitter against the Chicago White Sox at U.S. Cellular Field.

[33] After the no-hitter, Liriano made several strong appearances, including an exceptional start on June 12 against the Texas Rangers.

[1] On July 28, 2012, Liriano was traded to the Chicago White Sox in exchange for Eduardo Escobar and Pedro Hernández.

[1] On August 1, 2016, the Pirates traded Liriano along with Reese McGuire and Harold Ramírez to the Toronto Blue Jays for Drew Hutchison.

[56] Liriano made his debut with the Blue Jays on August 5, pitching six innings against the Kansas City Royals and yielding two earned runs in a 4–3 win.

[57] He appeared in 10 games (eight starts) with the Blue Jays to close out the season, and posted a 2–2 record, 2.92 ERA, and 52 strikeouts in 491⁄3 innings.

[59] During the eighth inning in the second game of the ALDS, Rangers outfielder Carlos Gómez hit a 102-mph line drive single that struck Liriano near the back of the head.

[61] On July 31, 2017, the Blue Jays traded Liriano to the Houston Astros for Nori Aoki and Teoscar Hernández.

[71] He was released on July 18,[72] and on August 2, Liriano opted out of the 2020 season due to the COVID-19 pandemic, although he had "multiple guaranteed offers" on the table.

[73] On February 2, 2021, Liriano signed a minor league contract with the Toronto Blue Jays, and was invited to spring training.

[1] Liriano's arrival in the United States for 2008 spring training was delayed due to visa problems caused by a prior drunk driving arrest in 2006.