The main protagonist of the novel is Dr. Elliott Grosvenor, the only Nexialist on board (a new discipline depicted as taking an actively generalist approach towards science). It is Grosvenor's training and application of Nexialism rather than the more narrow-minded approaches of the individual scientific and military minds of his other shipmates that consistently prove more effective against the hostile encounters both from outside and within the Space Beagle . He is eventually forced to take control of the ship using a combination of hypnotism, psychology, brainwashing, and persuasion, in order to develop an effective strategy for defeating the alien entity Anabis and saving the ship and our galaxy.
The book can be roughly divided into four sections corresponding to the four short stories on which it was based:
In the first section, the Space Beagle lands on a largely deserted desolate planet. Small scattered herds of deer-like creatures are seen, and the ancient ruins of cities litter the landscape. Coeurl, a starving, intelligent and vicious cat-like carnivore with tentacles on its shoulders, approaches the ship, pretending to be an unintelligent animal, and quickly infiltrates it. The creature kills several crewmen before being tricked into leaving the now spaceborne ship in a lifeboat. It then commits suicide when it realizes it has been defeated.
In the second part, the ship is almost destroyed by internal warfare caused by telepathic contact with a race of bird-like aliens, called Riim. The benign signals that the Riim send are incompatible with the human mind. Only Grosvenor's knowledge of telepathic phenomena saves the ship from destruction.
In the third section, the ship comes across Ixtl, a scarlet being floating in deep space. It is a vicious survivor of a race that ruled a previous universe before the Big Bang, the creation of our own universe. Ixtl boards the ship, and being obsessed with its own reproduction, kidnaps several crew members in order to implant parasitic eggs in their stomachs. It is eventually tricked into leaving the ship, after all the crew have left the ship temporarily, leaving no prey left for its offspring to feed on.
In the last section, Anabis, a galaxy-spanning consciousness, is encountered. Once again, it is both malevolent, starving and aggressive, and under all circumstances must be prevented from following the ship back to any other galaxy. Anabis, which is essentially a galaxy-size will-o'-the-wisp, feeds off the death of living organisms, and has destroyed all intelligent life in its galaxy. It transforms all planets it can find into jungle planets through terraforming, since it is these kind of worlds that produce most life. The crew of the Space Beagle lures the intelligence to chase the ship into deep space, causing it to starve to death.
Running concurrently to this, the book also covers a power struggle on the ship among the leaders of individual scientific and military groups.