The 6-foot-3, 210-pound Simms, the son of former New York Giants quarterback Phil Simms and younger brother of ex-Texas and NFL quarterback Chris Simms, would likely have entered spring practice as the Cardinals' starter under center.
A redshirt freshman, Simms was the backup to Hunter Cantwell this season after serving a four-game suspension for an undisclosed violation of team rules. He appeared in two games, completing four of 10 passes for 39 yards with an interception.
There was no immediate word on where Simms would transfer, but sources indicated he was leaning toward the junior college route.
Simms' departure leaves Louisville with no experienced quarterbacks and facing a wide-open competition for the starting job in the spring and fall. The candidates include junior Tyler Wolfe, NC State transfer Justin Burke, junior college transfer Adam Froman and freshman Zack Stoudt.
Brian Bennett covers the Big East for ESPN.com.