In Medal of Honor: Vanguard players play as Corporal Frank Keegan from the 82nd Airborn Division during World War II. He has been dropped behind enemy lines and needs to complete several missions in Italy, France, the Netherlands and Germany. He fights alongside AI colleagues in order to free Europe.

During these missions anti-aircraft weapons need to be blown up, fellow soldiers have to be rescued and enemy tanks need to be taking out using bazookas. Players are able to customize their weapons by adding a scope or a larger ammo drum. Similar to Medal of Honor: Airborne, during certain missions players parachute onto the battlefield and can choose from which starting location to complete the mission. There is no vehicle-based gameplay in this version.

Alongside the single-player campaign there is also 5 split-screen multiplayer mode for up to 4 players: Deathmatch, Team Deathmatch, Capture the Flag, King of the Hill and Scavenger Hunt. No online gameplay is supported.