Leftwich turned his right ankle in practice on Thursday. He called the injury "minor" but did not practice on Friday, when he was listed as questionable.
He missed 10 games with Jacksonville last season with an injury to his left ankle.
Leftwich relieved starter Joey Harrington in the fourth quarter of the Falcons' loss at Tennessee last week, renewing speculation he might win the starting job. On Monday, coach Bobby Petrino said Leftwich had moved up to No. 2 on the depth chart.
Atlanta's inactive list also included offensive tackle Todd Weiner, who had arthroscopic knee surgery on Wednesday and is expected to miss two to six weeks.
Linebacker Travis Williams, signed from the practice squad this week, was active.
New York's inactive list included receiver Steve Smith, who missed his fourth straight game since suffering a shoulder injury against Green Bay on Sept. 17. Smith had three catches against Dallas as the team's third receiver in its season opener on Sept. 9.
Anthony Wright was the Giants' backup quarterback for the fourth straight week, again leaving Jared Lorenzen as the third quarterback. Lorenzen was the backup the first two games before falling behind Wright on the depth chart.
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This is a matchup of two teams headed in opposite directions. The Giants have won three games in a row and now look like playoff contender, while Atlanta continues to struggle and now seems to have a quarterback controversy. The Falcons bring back Joey Harrington as the starter this week, but they will go with Byron Leftwich if he falters?
The questions for New York are whether Eli Manning will continue to show improvement and if he can lead the team effectively on a weekly basis. Will the Giants run game and aggressive blitz package continue to have success? Can the Falcons handle the defensive pressure that the Giants will bring? These are all questions that will be answered on Monday night.