Serious Sam Advance received mixed reviews, with praise for its weapons, enemies, level design and sound effects, conflicting opinions about its graphics, and criticism for its controls and frame rate issues.

The player, as Sam "Serious" Stone, can freely navigate each room, using the D-pad for forward and backward movement and the shoulder buttons for strafing.

[3] Serious Sam Advance contains no measures to save progress and uses a password system to let the player access later levels after a restart.

Using this feature, agents were sent to various ancient civilisations to investigate whether Mental—the antagonist in the Serious Sam series—was trying to release his horde on them to alter the course of history.

Sam, the only survivor from previous encounters with Mental's forces, was thus selected to travel to ancient Rome in 512 BCE.

Sam enters a Time-Lock with the intent to return home, but Mental interferes and sends him to ancient Rome instead.

In it, Sam eliminates the Wolfinator, marking the end of Mental's attempt to rule over ancient Rome.

[2][3] Jes Bickham, writing in NGC Magazine, commented that, due to the frame rate issues, the game was "slow and jittery, and ultimately workmanlike and tedious".

He stated that the music was "forgettable", while the sound effects for weapons and monsters were in good synchronicity with the gameplay.