Van Helsing's gameplay bears similarity to the Devil May Cry series by Capcom. Van Helsing begins the game wielding two handguns and his Tojo blades. He later acquires various other weapons, some of which are seen in the movie, such as the shotgun and the bow gun. Van Helsing can make use of both his firearms and his blades to dispatch enemies. The player also has the ability to use enhanced ammunition with Helsing's weapons once the ammo is found. Hitting the L1/LT trigger gives Van Helsing a blue-ish glow as he unloads his enhanced ammo. Van Helsing also can perform evasive rolls in four directions to avoid incoming attacks. Van Helsing also has a grappling hook that allows him to latch onto high ledges that are otherwise inaccessible. Van Helsing can make use of this grappling hook to start combos or to perform grappling jumps.
The game also features a shop mechanic where players can purchase additional combat techniques and power-ups to increase health and other characteristics. Items in the shop can be purchased by using "orbs" that are collected from fallen enemies.
The players can even collect the hat after having it knocked off by sustaining a hit from enemies and get points for retrieving the hat prior to completing a mission.