Lance was selected third overall by the San Francisco 49ers in the 2021 NFL draft, but limited play and injuries led to him being traded after two seasons to the Cowboys.

[9] The Bison were scheduled to make up the rest of the season in early 2021, but Lance announced following the game that he would opt out to prepare for the 2021 NFL draft.

[17][18] Lance began the 2021 season as the second-string quarterback behind incumbent starter Jimmy Garoppolo, but made his NFL debut in Week 1 against the Detroit Lions.

Lance was used in one play during the first quarter, in which he contributed to the eventual 41–33 road victory by throwing a five-yard touchdown pass to wide receiver Trent Sherfield.

[24] The injury made him unavailable for the Week 7 matchup against the Indianapolis Colts, with Nate Sudfeld replacing Lance as the second option behind a returning Garoppolo.

[27] Lance remained the second-string quarterback for the next five weeks until Garoppolo suffered a thumb injury during a 20–17 road loss to the Tennessee Titans.

[30] Following the season, Lance revealed he spent the year battling a right index finger injury he suffered in a preseason game against the Las Vegas Raiders.

[31] Lance was named the starter over Garoppolo for the 2022 season, but appeared in only two games before suffering a season-ending ankle injury against the Seahawks in Week 2.

[36] Lance entered the 2023 training camp on uncertain terms due to his limited play with the 49ers and the success of second-year quarterback Brock Purdy the previous season, who helped lead the 49ers to the 2022 NFC Championship Game.

[37][38] Ahead of the season, Lance was named the third-string backup behind Purdy and free agent acquisition Sam Darnold, which led to further speculation over his future in San Francisco.

He made his Cowboys regular season debut the following week against the Philadelphia Eagles, replacing an ineffective Rush in the fourth quarter.