During the course of the raid, all members of Rogan's team are killed except for his second-in-command, Captain Dan Taylor; both agents continued with the mission and reach a giant laboratory, where they find the source, but are attacked by the Death, a gigantic zombie security guard protecting the facility, who kills Taylor.

They are met by the same individual who approached Rogan in the prologue, revealed to be Daniel Curien, who laments his father's experiments that destroyed the world.

When they reach the same giant laboratory where Rogan was injured, Daniel reveals that the Wheel of Fate is actually his father Dr. Curien's body, which underwent a 19-year resurrection process following his death by the Magician, adding that he hacked the program used in its creation some time prior to Lisa and G's arrival, in order to prevent it from being released and destroying the world, saying that the future belongs to the people who are still alive and fighting.

While playing the game on Xbox, the light gun controller released by Madcatz may be used; however, the traditional "shoot off-screen" reload was reintroduced in the Wii version.

In The House of the Dead III, the player is given options for navigating through the game prior to the start of most stages, ultimately going through the same areas with different results dependent on the order chosen.

If all rescue events are successful, players find crates in the room before the final boss that, when shot, drop a lot of bonuses and lives.

In this game, the bosses' weak point must be shot repeatedly to drain the "Cancel" bar and stop the enemy's attack.

In the previous games, bonus points could also be gained by shooting hidden objects such as a golden frog, or coin.

On the Xbox, PC, PlayStation 3 and Wii versions, there is a "Time Attack" mode where the player's lives come in the form of a timer, starting at 45 seconds.

Excellent, Good, Faster and Twin Shots give extra time, as do clocks in the background, successful rescue events and end-of-stage bonuses.

Early previews of the game utilized Cel shading for the graphical style, with vibrant colors and solid outlines.

[2] Later previews showed a modified art style, still utilizing, in the words of the developers, "lit, cel-shaded effects" but with "a more realistic polygonal form.

[10] The Cincinnati Enquirer gave the Xbox version a score of three-and-a-half stars out of five and praised it for "the ability to mow down multiple enemies at once, enhanced graphics, a variety of endings and new creatures.