The Mariners promoted Smith to the major leagues on September 1, 2014. He faced one batter that day, retiring Josh Donaldson of the Oakland Athletics on a ground out. Smith made a total of nine appearances for the Mariners in September; he did not allow a run in innings pitched, while recording ten strikeouts and issuing three walks.
2015
Pitching for Seattle in 2015, Smith did not allow a run in his first 11 appearances of the season. This set a Mariners' record of 20 pitching appearances without allowing a run to start an MLB career. Smith finally allowed a run on May 3, his 21st MLB appearance, giving up a solo home run to Evan Gattis of the Houston Astros. Smith became the Mariners' closer in June due to Fernando Rodney's struggles during the season. For the season, Smith appeared in 70 Mariners games, compiling a 2.31 earned run average while recording 13 saves; in 70 innings pitched, he had 92 strikeouts and issued 22 walks.
On March 22, 2016, while pitching in spring training against the Miami Marlins, Smith was removed from the game after throwing five pitches during the 7th inning due to tightness in his right forearm. He was diagnosed with a flexor mass musclestrain after undergoing an MRI scan. Smith made three appearances for the Red Sox during the regular season, pitching scoreless innings in May while striking out two and walking one before landing back on the disabled list on May 20 with an elbow injury. He then underwent Tommy John surgery, ending his season. His return was not expected until June 2017.
2017
After more than a year recovering from surgery, Smith was sent on rehabilitation assignments in August 2017 with the Double-A Portland Sea Dogs and Triple-A Pawtucket Red Sox. He was then activated from the 60-day disabled list on September 5, 2017. He appeared in eight regular season games for Boston during September, giving up one run in innings pitched while striking out seven and walking two. Smith was included on Boston's postseason roster for the 2017 American League Division Series. He made two appearances during the series, pitching innings of scoreless relief, striking out one and walking two, as Boston lost to the eventual World Series champions, the Houston Astros.
2018
Smith entered the 2018 season as a member of the Red Sox' bullpen. On May 15, he was placed on the 10-day disabled list with a right shoulder subluxation. The injury occurred when Smith, in reaction to allowing a home run to Khris Davis of the Oakland Athletics in the prior day's game, threw his glove in the dugout out of frustration. Prior to being placed on the disabled list, Smith had made 18 appearances with a 1–1 record and 3.77 ERA. On June 12, it was revealed that Smith would require surgery for his shoulder injury, likely putting him out of action for the remainder of the year. The procedure was performed on June 13. The Red Sox outrighted him to the minors on November 1, 2018, and he chose to become a free agent.
2019
On December 30, 2018, Smith re-signed to a minor league deal with the Red Sox. He began with 2019 season on the injured list of Triple-A Pawtucket. Smith was released on June 18, 2019, without appearing in a game due to his ongoing recovery from shoulder surgery.
