Grimes had been listed as questionable and practiced on a limited basis but had been expected to play. However, the team elected to make him inactive Sunday morning.
Dominique Franks will start in Grimes' place and Christopher Owens will be the third cornerback.
Grimes has missed four of the past five games because of a sore right knee. The 2010 Pro Bowl alternate pick underwent minor surgery in late November and didn't return until the Falcons' blowout loss Dec. 26 at New Orleans.
Meanwhile, Giants tight end Jake Ballard is active and will start as expected. Ballard had missed the previous two games with a PCL knee injury.
Falcons starting linebacker Stephen Nicholas also will miss the game. That was expected because Nicholas was listed as doubtful with a toe injury and did not practice at all during the week. Spencer Adkins will start in his place.
There were no surprises for the Giants on the game-day inactive list. Linebacker Mark Herzlich (ankle), wide receiver Ramses Barden, running back Da'Rel Scott, offensive lineman James Brewer, center Jim Cordle, defensive end Justin Trattou and defensive tackle Jimmy Kennedy are inactive.
The Giants (9-7) are returning to the postseason after a two-year absence, while the Falcons (10-6) are in the playoffs for the second straight year and third time in four seasons.
Pat Yasinskas covers the NFC South for ESPN.com. Information from ESPNNewYork.com's Ohm Youngmisuk and The Associated Press was used in this report.