The game was announced in April 2018, originally as Serious Sam 4: Planet Badass, and was released in September 2020 for Microsoft Windows and Stadia, followed by PlayStation 5 and Xbox Series X/S ports in December 2021.

Players can also pilot multiple mechs that appear throughout the game, which are armed with machine guns and rocket launchers.

An unknown amount of time before the events of Serious Sam 3: BFE, a massive portal opens in Tunguska, Russia which serves as a bridgehead for Mental's forces to invade Earth.

As the whole planet scrambles to repel the alien invasion, a unit from the Earth Defense Force led by "Serious" Sam Stone is sent by General Brand to Rome to meet Father Mikhail, a priest who claims to have found some clues leading to the Holy Grail, which, according to him, is a powerful alien artefact hidden inside the Ark of the Covenant that may aid them against the invasion.

In order to get back to the city, Sam and his companions retreat to Pompeii, where they remotely use the seismic capabilities of the HAARP complex to trigger an eruption on Mount Vesuvius that disrupts Achriman's air forces.

Upon returning to Rome, Sam meets a gun-toting old lady called Nonna who provides him directions to the Vatican, which Father Mikhail believes contains the next clue to the Grail.

At the site of the superportal in Tunguska, Sam finds that his friends have also escaped from Brand and joins them in a large-scale battle between the EDF and the alien forces.

Brand recaptures Sam and offers both him and the artefact as gifts to Ugh-Zan VI, one of Mental's most powerful warriors, but the alien rejects him.

With help from his friends, Sam kills Ugh-Zan VI with the artefact and straps Brand to an ICBM that the team then launches into the portal, destroying it.

[6][7] In September 2015, The Talos Principle co-writer Jonas Kyratzes and his wife, Verena, were announced as the screenwriters for Serious Sam 4.

[15] Devolver Digital stated that, due to an exclusivity deal with Stadia, versions for PlayStation 4 and Xbox One had been postponed to early 2021.