The Detroit Tigers drafted Smyly in the second round of the 2010 MLB draft. He signed with the Tigers, receiving a $1.1 million signing bonus. Pitching for the Lakeland Tigers of the Class A-Advanced Florida State League and the Erie SeaWolves of the Class AAEastern League, Smyly was named the Tigers Minor League Pitcher of the Year in 2011, pitching to an 11–6 win–loss record in 22 games with a 2.07 earned run average and 130 strikeouts in 126 innings pitched. He was also FSL Pitcher of the Week on June 13, and an MiLB.com Tigers Organization All-Star.
2012
Heading into the 2012 season, MLB.com ranked Smyly the 82nd-best prospect in baseball, while Baseball America ranked him the third-best prospect in the Tigers organization, behind Jacob Turner and Nick Castellanos. The Tigers invited Smyly to spring training in 2012, allowing him to compete for a spot in the Tigers starting rotation. Smyly won the competition, beginning the 2012 season in the starting rotation of the Detroit Tigers, though he made one start with the Toledo Mud Hens of the Class-AAAInternational League on April 7 prior to being called up for his MLB debut on April 12. On June 14, he was placed on the disabled list due to a blister on his left hand. Following the Tigers trade deadline acquisition of starter Aníbal Sánchez from the Miami Marlins, Smyly spent much of August and September coming out of the Tigers bullpen. On the season, he pitched 99 innings, compiling a 4–3 record with 94 strikeouts, 33 walks, and a 3.99 ERA. He was named to the Tigers postseason roster. Smyly was the winning pitcher in Game 1 of the 2012 ALCS against the New York Yankees, pitching the final two innings of the Tigers’ extra-innings win.
2013
Smyly competed with Rick Porcello in spring training for the fifth spot in the Tigers 2013 starting rotation. On March 26, it was announced that Porcello had won the No. 5 starter job, and that Smyly would start the season in the Tiger bullpen. On April 5, Smyly got his first career save after pitching four perfect innings of relief in an 8–3 win over the Yankees. In his first full season as a reliever, Smyly posted a 6–0 record with 2 saves in 63 games with a 2.37 ERA. He led all Tigers relievers and all AL lefty relievers in innings pitched and strikeouts.
2014
With the departure of Tigers starter Doug Fister via trade, he was named the No. 5 starter in the Tigers rotation for the 2014 season. Because of off days, he pitched six innings out of the bullpen before making his season debut as a starter on April 18. He pitched seven shutout innings to earn the win in a May 3 game against the Kansas City Royals. This marked his first win as a starter since July 6, 2012, which also came against Kansas City. On July 25, in a game against the Los Angeles Angels of Anaheim, Smyly matched his season high in strikeouts after just three innings, and finished the game with a career-high 11 strikeouts in 5 innings.
Tampa Bay Rays
On July 31, 2014, the Detroit Tigers traded Smyly to the Tampa Bay Rays, along with Willy Adames, in a three-team deal that also sent Austin Jackson to the Seattle Mariners, Nick Franklin from the Mariners to the Rays, and David Price to the Tigers. On September 9, Rays' manager Joe Maddon announced they would shut down Smyly for the remainder of the season, after he had pitched a career-high 153 innings. After being traded to the Rays, Smyly went 3–1 with a 1.70 ERA in seven starts. Opponents hit.155 against him, a figure that led the AL over that span. For the 2014 season he was 9–10 with a 3.24 ERA in 28 games, 25 of which were starts. In 2015 he was 5–2 with a 3.11 ERA in 12 starts, as he struck out 77 batters in 66 innings. On February 4, 2016, Smyly won his arbitration case against the Rays. He earned $3.75 million in 2016. In 2016 he was 7–12 with a 4.88 ERA in 30 starts in which he pitched 175 innings. The 32 home runs he gave up were fifth-most in the American League.
On December 12, 2017, Smyly signed a two-year, $10 million deal with the Chicago Cubs. During the 2018 season, after recovering from his surgery Smyly made a single appearance in the minor leagues, pitching one inning for the Class ASouth Bend Cubs, striking out three.
Texas Rangers
On November 2, 2018, the Cubs traded Smyly and a player to be named later to the Texas Rangers in exchange for a player to be named later. He was placed on the disabled list on April 20 with a left arm injury. On June 20, he was designated for assignment. On June 25, he was released by Texas. For the portion of the 2019 season that he pitched for Texas, he was 1–5 with an 8.42 ERA in 13 games, 9 of which were starts, as he struck out 52 batters in 51 innings.
On July 1, 2019, Smyly signed a minor league deal with the Milwaukee Brewers. Starting three games for the AAA San Antonio Missions, he was 1–0 with a 4.97 ERA with 18 strikeouts in 12 innings. He elected free agency on July 18.
Philadelphia Phillies
On July 21, 2019, Smyly signed a major league contract with the Philadelphia Phillies. With the Phillies he was 3-2 with a 4.45 ERA, as in 12 starts, he pitched innings and struck out 68 batters; the 32 home runs he gave up for the season between Texas and Philadelphia were the 10th-most in the major leagues.
San Francisco Giants
On January 16, 2020, Smyly signed a one-year deal with the San Francisco Giants.
Smyly throws four pitches. His main pitch is a four-seam fastball at 91 mph, known for the fact that it explodes on the hitter. He adds a curveball at 77 with little depth. He has a cut fastball around 87, which has drawn praise for its late, darting movement into right-handed hitters and away from lefties. Since 2014, he has re-added a changeup in the 83 mph range that he throws almost exclusively to right-handed hitters. He will also mix in a slider on occasion.
