Elements of this game take inspiration from Serious Sam: Next Encounter; both games start off in Italy, both games have a combine harvester as a vehicle, both games have a weapon that fires a concentrated laser beam, the rocket launcher in Next Encounter has an alternate firing mode that fires homing rockets, and likewise, Serious Sam 4 offers an attachment to the rocket launcher that also allows it to fire homing rockets, the sniper rifle in Serious Sam 4 also shares a similar design to the sniper rifle in Next Encounter, and the inspiration continues in the expansion pack, Siberian Mayhem, where in that game, there is a new tank vehicle that behaves very similar to the armored car vehicle in Next Encounter, and Siberian Mayhem also introduces the new Octanian Legionnaire enemy, which looks and behaves very similar to the Porcine Berserker enemy from Next Encounter.
The cloned soldiers, antarisian spiders and aurigan cave demons are the only enemies from Serious Sam 3 that do not appear in this game. The former two enemies are instead with replaced with new enemies with very similar characteristics, known as the octanian soldiers and the zubenhakrabian spiders.