Stan, Zev and Kai accidentally steal the Lexx, the most powerful weapon of destruction in the two universes. After successfully fleeing from the Cluster, the main planet of the League of the 20,000 Planets, they are looking for a new home. Kai needs protoblood to live outside of his cryochamber. Looking for protoblood, the Lexx returns to the Cluster to learn that a huge insect survived. This insect had controlled The Divine Order and His Divine Shadow in order to eat all human inhabitants of the 20,000 planets. The insect then begins a metamorphosis into the Gigashadow. Gigashadow produces protoblood. With the help of Zev, Kai manages to fill up his store of protoblood. Kai places the cluster lizard Squish in the brain of the insect and thus is able to destroy it.

The main conflict of the second season is the fight against Mantrid, the former Bio-Vizier of His Divine Shadow. The crew had inadvertently helped him transfer his mind into a machine in the first episode of the season while accidentally fusing it with a remnant of His Shadow. Mantrid's goal is to transform all matter in the Light Universe into Mantrid Drones. In the meantime the crew keeps getting into difficult situations and is usually rescued by Kai. At the end of the season they destroy Mantrid. Unfortunately, the Light Universe is also destroyed. The crew flees into the Dark Zone.

The Lexx is running out of food and must fly slowly to conserve energy. 790 computes that it might take thousands of years to reach an inhabited planet. The crew enters cryostasis to survive the voyage. After 4,000 years in cryostasis, they reach the twin planets Fire and Water. The entire third season takes place on these two planets. The crew meets people they knew from the Light Universe. These survivors cannot remember their past in the parallel universe, though their personalities are still the same. Fire is ruled by the charismatic Prince. Water doesn't seem to have a ruler. The inhabitants of both planets live in isolated towns. On Water they live on islands in a huge ocean and on Fire, there are massive towers separated by long stretches of desert.

The Lexx travels to Earth looking for food. It is located in the very center of the Dark Universe and the crew assumes that it must be a very dangerous place. The crew again meet people they knew from the Light Universe, and from Fire and Water. Only Prince and Priest are able to remember their lives on Fire. The Earth is threatened by a being who resembles Lyekka. The crew finds out that the fake "Lyekka" destroyed all human life on her way through the Dark Zone. Kai decides to destroy the asteroid that is the source of the entity. Prince keeps his promise and restores Kai's mortality.