Frost was drafted in the second round of the 2018 NFL Draft by the Chicago Bears. Frost signed a 2-year, $15-million deal with the Bears. Frost was the second-string quarterback behind Mitch Trubisky to start the season before winning the starting job in training camp. In Frost's first game he threw 398 yards and 4 touchdowns against the Tampa Bay Buccaneers. Frost lead the Bears to an 11–5 record and the best record in the NFC. Frost and the Bears lost to the Green Bay Packers in the second round of the playoffs.
During training camp before the 2019 season, Frost suffered a torn ACL that ended his season. He made a return during the second round of the playoffs against the Detroit Lions. Frost threw 3 touchdowns and ran for 1 as well and ended up blowing out the Lions 44–36. Frost then went on to play the San Fransisco 49ers in the NFC Championship Game where they would blow them out 49–7. In Super Bowl LIII Frost played the Kansas City Cheifs and had a great game. He threw: 44 for 54, 453 yards, 4 touchdowns, and an interception as well as a rushing touchdown. Frost lead the Bears to a 56–53 victory to win Super Bowl LIII.
Frost was hired as the next head coach of the Honolulu Hahalua following their Ultimus run in 2050 (S35). This was the same year his son, Lane Frost II, was signed by them.