In the Pirates’ first playoff game in 21 years, Liriano gave up one run and four hits in 7.0 innings while earning the win as the Pirates defeated the Reds 6–2 in the NL Wild Card game. He thus became the first Pirates pitcher to win a postseason game since Tim Wakefield in 1992, as well as the first pitcher to win a postseason game at PNC Park. Liriano was named the 2013 NL Comeback Player of the Year for his bounce back year.

Liriano struggled through his first several starts of 2011, giving up 24 earned runs in 23.2 innings through the Month of April. During this period of 5 starts, he only entered the 7th inning once. He met with his pitching coach and manager after these starts and was in danger of losing his spot in the starting rotation. His fortunes changed significantly in his next start. 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. The no-hitter featured 6 walks, a high (although not record-high) number for a no-hit game. He struck out 2 of the 30 batters he faced and threw 123 pitches, 66 of which were strikes. It was the first no-hitter for the Twins organization since Eric Milton accomplished the feat on September 11, 1999, against the Anaheim Angels, and the seventh official no-hitter for the franchise.

Liriano signed with the San Francisco Giants as an international free agent in 2000. 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. Pierzynski.

Often compared to former teammate Johan Santana, another hard-throwing lefty, Liriano was touted as one of the “super-prospects” within the Twins organization. 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. He led all minor league pitchers in strikeouts that year, with 204. He made his major league debut in relief on September 5, 2005, against the Texas Rangers. He later joined the Twins’ starting rotation and won his first game on September 30, 2005, against the Detroit Tigers. Liriano started the 2006 season in Minnesota’s bullpen, but was promoted to the starting rotation in May, exchanging positions with struggling starter Carlos Silva. He won each of his first three starts.

Liriano led the Major Leagues with a 2.19 ERA, statistics putting him in discussion for both the American League Cy Young and Rookie of the Year awards, but a trip to the disabled list on August 11 left him with too few innings to qualify as the league’s official ERA leader and jeopardized his chances at any such awards in 2006. On August 1, 2006, Liriano was scratched from his scheduled August 2 start because of forearm inflammation after a bullpen session. He missed one start before resuming bullpen work without pain, but was placed on the disabled list after continued arm pain during his last start on August 7, 2006. Liriano began a rehabilitation program on August 22, and threw off a mound for the first time on August 30, throwing only his fastball and changeup, and said that he would like to pitch his breaking ball later that week. He made a rehab start for the Rochester Red Wings on September 9, throwing 40 pitches for four strikeouts and one walk in three shutout, hitless innings. After the game, he reported feeling no pain in his elbow and was reactivated by the Twins.

On November 6, 2006, Liriano underwent Tommy John surgery to curtail the pain in his left elbow. He missed the entire 2007 season.

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. Francisco and Johanna Liriano became parents to Kevin Liriano on April 4, 2008. Liriano is the first cousin of pitcher Santiago Casilla.

On April 11, 2008, he was recalled from Triple-A Rochester in the place of injured pitcher Kevin Slowey. Liriano made his season debut and his first game since Tommy John surgery on April 13, against the Royals. He pitched 4.2 innings giving up six hits, four earned runs and walking five while picking up a loss.

Liriano posted a less than stellar 5–13 record in 2009, with a combined ERA of 5.80. However, this was his first year since his Tommy John surgery that he had spent that entire year on the Twins major league roster. On June 28 against the St. Louis Cardinals, he threw seven strong innings, only surrendering two runs. On August 12 vs Kansas City, Liriano went another seven innings, only allowing one Royals player to score a run in yet another strong outing. Between those strong flashes of brilliance though, he logged several sub-par showings, frequently giving up several runs during short times on the mound.

During the 2009 offseason, Liriano returned to his native Dominican Republic to play winter baseball, playing for Leones del Escogido. 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 finished 2010 fifth in the AL in strikeouts with 201, while walking 58. He posted a 14–10 record for the year with a 3.62 ERA and a career-high 191 ⁄3 innings pitched across 31 starts, 20 of which were quality. He was considered a Cy Young candidate by some writers, as his 2.66 FIP (a defense independent pitching statistic) was second only to Cliff Lee in the American League, and his 2.95 xFIP was first in the American League. Despite his ERA only ranking 14th in the league, Liriano posted an extremely low FIP primarily due to his ability to limit home runs. Liriano only allowed nine across the entire regular season (three of which came in his final start) and his HR/9 rate of 0.42 led the American League (which was also the lowest rate posted by a Twins starter in over 20 years). He was further benefited by his high strikeout totals, as his K/9 ratio of 9.44 ranked second in the AL behind Jon Lester and he was one of only five AL pitchers that year with at least 200 strikeouts.

After the no-hitter, Liriano made several strong appearances, including an exceptional start on June 12 against the Texas Rangers. He retired the first 19 batters in order and didn’t give up a hit until the 8th inning. Liriano’s performance faded later in 2011. After an exceptional outing against the New York Yankees, he left his next start on August 25 after just two innings. He made his way to the disabled list with shoulder strain and did not start another game for the rest of the year. He finished the season with a record of 9–10 and an ERA of 5.09.

Liriano pitched a four-strikeout inning in the fourth inning of the Twins’ game against the Kansas City Royals on June 5, 2012. On July 13, he struck out 15 batters in a loss to the Oakland Athletics, topping his career high of 12 strikeouts. He caused 27 swing and misses, the highest number since 2007. In 22 games (17 starts) with the Twins in 2012 before he was traded, Liriano went 3–10 with a 5.31 ERA and 109 strikeouts.

On July 28, 2012, Liriano was traded to the Chicago White Sox in exchange for Eduardo Escobar and Pedro Hernández. As Liriano struggled with the command of his pitches, the White Sox removed him from the rotation in September. In 12 games (11 starts) with the White Sox, he went 3–2 with a 5.40 ERA.

Liriano agreed to a two-year contract with the Pittsburgh Pirates on December 21, 2012. The contract was voided shortly after as he suffered an injury to his non-throwing arm and failed his physical, having broken his non-throwing arm while he tried to scare his kids at Christmas. A new two-year deal was reached between the Pirates and Liriano and became official on February 8, 2013. He started the 2013 season on the Pirates’s 15-day disabled list. He made his debut on May 11 against the New York Mets. Liriano’s improved command by changing his pitching mechanics led to a career rebirth with Pittsburgh. He finished his 2013 campaign with a record of 16–8, an ERA of 3.02, and 163 strikeouts.

As of 2012, Liriano is a four-pitch pitcher. To left-handed hitters he throws a four-seam fastball, a two-seam fastball (both averaging about 93 mph), and a slider (mid 80s). Against right-handers, he adds a mid-80s changeup. More than half of his pitches with 2 strikes are sliders, perhaps due to the relatively high whiff rate — 43% over his career. He has one of the league’s highest whiff rates on a slider with 2 strikes.

Liriano struggled greatly in the first half of the season, going 1–7 with a 4.72 ERA in 15 starts at the All Star break. However, he reclaimed his dominance of 2013 in the second half of the season, going 6–3 with a 2.20 ERA in 14 starts to end the season. Overall, Liriano posted another strong season in 2014, going 7–10 with a 3.38 ERA and 175 strikeouts in 29 starts. On December 9, 2014, he re-signed with the Pirates on a 3-year, $39MM contract.

On August 1, 2016, the Pirates traded Liriano along with Reese McGuire and Harold Ramírez to the Toronto Blue Jays for Drew Hutchison. While it was initially believed that Liriano would replace Aaron Sanchez in the rotation due to the organization’s desire to limit Sanchez’s workload, general manager Ross Atkins announced on August 4 that the Blue Jays would use a six-man rotation going forward. 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. He made eight starts and two relief appearances with the Blue Jays in the regular season, and posted a 2–2 record, 2.92 ERA, and 52 strikeouts in 49⁄3 innings. In 2016 between the two teams he had the highest rate of bases on balls per 9 innings pitched in the majors (4.69).

On June 25, 2017, Liriano earned the 100th win of his career in an 8–2 victory over the Kansas City Royals.

On July 31, 2017, the Blue Jays traded Liriano to the Houston Astros for Nori Aoki and Teoscar Hernández. Liriano was moved from the rotation to the bullpen following his acquisition. He made 20 appearances out of the bullpen and finished with an 0–2 record with a 4.40 ERA. Overall in 2017, Liriano made 38 appearances (18 starts) with a 6–7 record and a 5.66 ERA. The Astros finished the year with a 101–61 record (first in AL West), and eventually won the 2017 World Series.

On February 23, 2018, Liriano signed a one-year contract with the Detroit Tigers. He earned a spot in the Tigers starting rotation, and won his Tiger debut in a 6–1 decision over the Kansas City Royals on April 2. Liriano was placed on the 10-day disabled list with a hamstring strain following a May 26 start against the Chicago White Sox. He was recalled on June 23 and made a start against the Cleveland Indians. On August 30, 2018, Liriano gave up Giancarlo Stanton’s 300th home run. Liriano made 26 starts for the 2018 Tigers, compiling a 5–12 record, 4.58 ERA, and 110 strikeouts in 133 ⁄3 innings.

On February 4, 2019, Liriano agreed to a one-year minor league deal with the Pittsburgh Pirates. Ken Rosenthal of the Athletic first reported the deal and it was later confirmed to be worth $1.5 million with an additional $1 million in incentives. On March 23, 2019, the Pirates announced that Liriano had made the opening day roster. He was used exclusively as a relief pitcher during the season, posting a 5–3 record with a 3.47 ERA and 63 strikeouts in 70 innings.

On January 22, 2020, Liriano signed a minor league deal with the Philadelphia Phillies. He was released on July 18.

On August 2, 2020, Liriano opted out of the 2020 season due to the COVID-19 pandemic, although he had “multiple guaranteed offers” on the table.