GameNight is a nightly sports talk radio show hosted by various personalities such as Doug Gottlieb, John Seibel, Freddie Coleman and Jeff Rickard. Produced by ESPN Radio, GameNight is the only show that has remained on the air since the station's debut. It airs every evening from 7 p.m. till 1 a.m. ET, except during baseball season when the show begins at 7:30 p.m. following Sunday Night baseball coverage. The six-hour show has two hosts each night. The program features in-game updates, guests ranging from superstars to experts, and in-depth analysis on the day's sports stories. It is broadcasted from ESPN Headquarters in Bristol, Connecticut.

Hosts Seibel and Rickard have also filled in for The SportsBash and AllNight with Jason Smith (both shows are also on ESPN Radio). Fill-ins for GameNight include John Rook and Amy Lawrence. The most notable former host is Chuck Wilson, who was on the program from its debut to July 2005, when his contract expired and was not extended. Other original hosts include sports personalities such as Keith Olbermann, Tony Bruno and Mike Tirico.

ESPN Radio SportsCenter is every twenty minutes throughout GameNight. The anchor on weekdays for GameNight is Jon Stashower until 10 p.m. ET and Jay Reynolds for the rest of the show and AllNight with Jason Smith. The normal weekend anchor is Marc Kestasher.