2021

Ahead of the 2021 NFL Draft, most analysts predicted Lance or Alabama quarterback Mac Jones would be taken third overall by the San Francisco 49ers, who traded up with the Miami Dolphins in exchange for their first-round picks in 2021, 2022, and 2023 and their third-round pick in 2022.^[14][15] The 49ers selected Lance, making him their first first-round quarterback since Alex Smith in 2005 and the second-highest drafted FCS player after fellow North Dakota State quarterback Carson Wentz.^[16] Considered a top quarterback prospect in the draft, Lance was one of five quarterbacks taken in the first round. He signed his four-year rookie contract, worth $34.1 million, on July 28, 2021.^[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. He was used in one play during the first quarter, in which he contributed to the eventual 41–33 victory by throwing a five-yard touchdown pass to wide receiver Trent Sherfield.^[19] In Week 3 against the Green Bay Packers, Lance took the field for two plays and scored a rushing touchdown on the first. The game ended in a 30–28 defeat.^[20]

During Week 4 against the Seattle Seahawks, Lance saw his first significant playing time when he relieved an injured Garoppolo in the second half. He completed 9 of 18 passes for 157 yards and two touchdowns and rushed for 41 yards on seven carries, with the 49ers ultimately losing 28–21.^[21] Due to Garoppolo's injury, Lance was named the starter for the following week's game against the Arizona Cardinals.^[22] Lance completed 15 of 29 passes for 192 yards, rushed for 89 yards on 16 carries, and threw his first interception on the 49ers' opening drive to safety Budda Baker in the 17–10 defeat.^[23] Following the game, it was announced Lance suffered a sprained knee.^[24] The injury made Lance unavailable for the Week 7 matchup against the Indianapolis Colts, with Nate Sudfeld replacing him as the second option behind a returning Garoppolo.^[25] He returned as Garoppolo's backup during the next week's 33–22 victory over the Chicago Bears.^[26] Lance did not take field again until the 49ers' final drive against the Jacksonville Jaguars in Week 11. He rushed for seven yards before taking the victory formation to complete the 30–10 win.^[27]

Lance remained the second-string quarterback for the next five weeks until Garoppolo suffered a thumb injury in a 20–17 loss to the Tennessee Titans. Making his second start in Week 17 against the Houston Texans, Lance threw for 249 yards, two touchdowns, and an interception. The 49ers won the game by a score of 23–7, earning Lance his first career win.^[28] Lance's start marked his final appearance in 2021 after Garoppolo returned for the regular season finale against the Los Angeles Rams.^[29] He held a backup role during the 49ers' playoff run, which concluded with a defeat to the Rams in the NFC Championship Game.^[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]

2022

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.^[32] His only full game of the season was the opener against the Bears, completing 13 of 28 passes for 164 yards and an interception in a 19–10 loss.^[33][34][35] Lance had a second surgery on his ankle to remove hardware causing irritation.^[36]

2023

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.^[39]