The series centered on the exploits of Vanth Dreadstar and his crew—powerful mystic Syzygy Darklock, the cybernetic telepath Willow, cat-like humanoid Oedi, and freebooter Skeevo. Vanth, newly arrived in the Empirical Galaxy after the events of Metamorphosis Odyssey, tries to live a pastoral existence on Oedi’s planet of peaceful cat-people, but his peace is disturbed by the arrival of Darklock, who wants him to get involved in the conflict between the two major forces in the galaxy, the Monarchy and the theocratical Instrumentality. Vanth refuses until the war comes to his planet, wiping out most of the population. Oedi survives and joins them; Willow and Skeevo join later, though the team is in place for the first issue.
Dreadstar takes the side of the Monarchy against the evil Lord High Papal of the Instrumentality, but his team end up becoming fugitives when the Monarchy falls, and go to great lengths to try to uncover a traitor in their midst. The transition to First Comics happened just when the traitor was about to be revealed, and the first issue published under First Comics, #27 contained this revelation.