DeSmith was named to the AHL's 2016–17 All-Rookie Team and was a co-recipient of the 2017 Harry "Hap" Holmes Memorial Award.

[2] Undrafted and regarded as undersized for a goaltender, he signed with the Wheeling Nailers, the ECHL affiliate of the Pittsburgh Penguins, in 2015 after his college career at the University of New Hampshire was halted due to legal problems.

After performing well both in Wheeling and while being loaned to the American Hockey League's Wilkes-Barre/Scranton Penguins later that season, he earned a promotion by signing an AHL contract in the summer of 2016.

DeSmith at first competed with Tristan Jarry and Matt Murray for NHL playing time; he spent the 2019–20 season in the AHL.

After being involved in two trades in the 2023 off-season, DeSmith played with the Vancouver Canucks in the 2023–24 season, signing with the Stars after the conclusion of his contract.

He pleaded not guilty to all charges against him (including domestic abuse) with the exception of a single count of disorderly conduct.

[citation needed] DeSmith would appear in just 13 games with the Nailers' 2015–16 Eastern Conference championship team, posting a 5–2–2 record, a 2.55 goals against average, and a .915 save percentage.

[citation needed] He earned his first win in his first career AHL start on January 3, against the Hartford Wolf Pack, stopping 22 of 24 shots.

The double overtime win clinched the Penguins' fourth division crown as the top-ranked team in the Eastern Conference.

On October 23, 2017, executive vice president and general manager Jim Rutherford announced that Pittsburgh had recalled DeSmith from Wilkes-Barre/Scranton.

He played in his first NHL game on October 29, against the Winnipeg Jets after head coach Mike Sullivan pulled starting goaltender Matt Murray in the first period.

[18] DeSmith was recalled on November 28, to play backup to Tristan Jarry after starting goaltender Matt Murray was injured.

[24] He recorded his first NHL career shutout on April 6, to help the Penguins clinch home ice advantage for Game 1 of the 2018 Stanley Cup playoffs.

[25] During the 2018–19 season, having established himself in the backup role for the Penguins, DeSmith was signed to a three-year, $3.75 million contract extension with Pittsburgh on January 11, 2019.

[27] In the 2020–21 season, which was shortened by the COVID-19 pandemic, DeSmith served as full-time backup to Jarry for the Penguins, compiling an 11–7–0 record in starts with a .912 save percentage.

DeSmith found himself in the spotlight when Jarry injured his foot shortly before the beginning of the 2022 Stanley Cup playoffs, elevating him to the starting goaltender position.

In his first NHL playoff start in Game 1 of the first round series against the New York Rangers, DeSmith made 48 saves on 51 shots in the course of regulation time and two periods of overtime.