The New York Giants have ruled out Saquon Barkley for Thursday's game against the San Francisco 49ers due to a sprained right ankle the star running back sustained Sunday against the Arizona Cardinals.

ESPN reported Monday that Barkley was expected to miss around three weeks after injuring his ankle in the latter stages of New York's 31-28 Week 2 win, though Giants coach Brian Daboll told reporters Tuesday the 2022 Pro Bowl selection was feeling better and the team had yet to make a determination on Barkley's status.

With Barkley unavailable, the Giants will have former 49er Matt Breida and Gary Brightwell as their top two running backs for Thursday's matchup.

Breida has spent the majority of his seven-year career as a backup, but did rush for 814 yards in 14 games with San Francisco in 2018. Brightwell's most extensive action came in the 2022 regular-season finale, in which he rushed for 60 yards on 11 carries against the Philadelphia Eagles. 

Neither has the credentials of Barkley, who finished fourth in the NFL with a career-high 1,312 rushing yards and scored 10 touchdowns in 2022 to help the Giants to their first playoff appearance in six years. The 26-year-old accounted for 27.7 per cent of New York's total yards from scrimmage last season, the sixth-highest rate of any player for his respective team.

Barkley also played a major role in Sunday's win, in which the Giants overcame a 21-point third-quarter deficit. The 2018 No. 2 overall pick had both a rushing and receiving touchdown in the second half and ended the game with 63 rushing yards on 17 carries along with six receptions for 29 yards.

The two-time Pro Bowler has been slowed by ankle problems in the past, however. Barkley missed three games in 2019 with a high ankle sprain and four in 2021 with an injury to his left ankle.

The Giants will also be without starting left tackle Andrew Thomas for a second straight game due to a hamstring injury he suffered in the team's season-opening 40-0 loss to the Dallas Cowboys.