It is the first game in the MLB: The Show franchise, after its predecessor series ended due to the formation of San Diego Studio from Red Zone Interactive and 989 Sports.

Ortiz, Don Zimmer, and Dave Campbell also appeared in TV spots advertising the game.

A unique aspect of the game mode is the user's controlling only one chosen player during gameplay, as opposed to the entire team.

Also featured in MLB 06: The Show is Franchise mode, where in addition to multiple 162-game seasons, users control every part of the team, such as hiring coaches and setting prices.

Users can sign free agents, deal with player contracts, and achieve franchise goals unique to each team.