Serious Sam Classic: The First Encounter begins with a prologue. It tells about the remains of an ancient civilization that was accidentally found during excavations in Ancient Egypt at the beginning of the twenty-first century. Everything indicated that they had come from the planet Sirius, and for some unknown reason they decided to stay. This discovery allowed humanity to greatly advance in science and the development of all kinds of technologies. People have discovered flights in intergalactic space. This provided new opportunities for research. On the threshold of the 22nd millennium, having reached the darkest corners of space, earthlings encountered one of the most powerful and dangerous criminals in the entire Universe. The tyrant named Mental turned out to be much stronger than anyone could have expected. Therefore, the astronauts were forced to return to Earth. All colonies were destroyed and destroyed. The only thing that could save humanity was the Key of Loyalty, still hidden in the excavated ruins.

The main character in Serious Sam Classic: First Encounter is Samuel Stone. He is sent back in time to change the course of events. The guy finds himself in 1378 BC. His main task is to travel to ancient sites and fight enemies. Often these creatures resemble mythical creatures like harpies.