Sirens of Titan tells the story of the wide-ranging journey of Malachi Constant, the wealthiest man on Earth, from Earth to Mars to Mercury, back to Earth, and finally to Titan, a moon of Saturn. Along the way, Constant is seemingly manipulated and controlled by Winston Miles Rumfoord, an American aristocrat whose existence has been scattered across time and space after flying into a warped region of the solar system while on a space flight to Mars. Rumfoord builds up a small civilization on Mars and leads it into a suicidal mission to take over Earth as a prelude to introducing a new religion on Earth that teaches that God is completely indifferent to the welfare of humankind. He uses Constant as a symbolic figure in this faith, and humiliates his erstwhile wife, Beatrice, in a grand spectacle during which the two of them are exiled on Titan along with their son, Chrono. Once on Titan, they learn from an extraterrestrial called Salo that even Rumfoord has been manipulated in a much larger scheme with the seemingly small purpose of providing Salo with a missing part for his space ship.

Winston Niles Rumfoord, after having flown his private space ship into something called a chrono-synclastic infandibulum, has had his existence stretched out into a spiral through time and space. This causes him to materialize and dematerialize at different places in the solar system at regular intervals. One of these places is within his large estate in Newport, Rhode Island, where his wife, Beatrice Rumfoord, lives. These materializations are known about by the public, but nobody has ever been allowed to witness one until now. The wealthiest man in the world, the playboy Malachi Constant, has been invited to meet Rumfoord at Rumfoord's specific request.

Constant's meeting with Rumfoord is disturbing. Rumfoord, who can read minds as well as see into the past and future, tells Constant that he and Beatrice will have a child together on Mars, and that Constant will travel from Mars to Mercury, then back to Earth briefly before ending up on Titan. Rumfoord tells Constant that there are beautiful women on Titan and gives him a photograph of three of them. Constant finds them stunning. These are the sirens of Titan.

Unable to accept Rumfoord's predictions, Beatrice and Constant do everything in their power to prevent them from coming true. It is no use, however. Constant soon loses all his wealth as his previously astoundingly lucky investment strategy fails him. Constant has been following the bizarre method of his father, who founded the company Magnum Opus, which has made Constant so rich. His father, Noel, simply wrote out the letters of the first sentence in the Gideon Bible in pairs, then invested in companies that had the same initials. Upon his death, Constant continues the same method, which works for a time but leads him into ruin. Facing bankruptcy and numerous lawsuits, when two Martian recruiters offer him a position as an officer in the Martian army which is preparing to invade Earth, Constant jumps at the chance.

Beatrice also faces financial ruin and is forced to sell the estate. The two buyers are actually the same Martian recruiters that have convinced Constant to join them. They trick Beatrice onto their ship and leave for Mars. Neither Beatrice nor Constant is aware the other is on board. Beatrice is kept locked away in her room on the journey and the swaggering Constant is told only that a beautiful woman is in the room. One night, Constant obtains the key to the room and enters it. He rapes Beatrice in the dark, startled to find afterward who she is. Thus the first of Rumfoord's predictions seems to be on its way to coming true.

On Mars, each of them have their memories erased and controlling antennas implanted. Constant is now called Unk, and is a soldier in the Martian Army. He is forced to take part in the execution of another soldier named Stony Stevenson, who, unbeknownst to Constant, is actually his own best friend. He has had his memory erased several times while on Mars because he seems to be able to remember to well. Beatrice, now called Bee, has a child, a boy named Chrono. She becomes a teacher.

As the Martian army is mobilized to invade Earth, Constant runs away to find Bee and Chrono. He does manage to find them, but is soon captured by the military police and taken to the spaceship that is to carry him and another soldier named Boaz to the fighting on Earth. As they are about to take off, Rumfoord reveals himself to them. It is learned that Rumfoord is the mastermind behind the invasion. He tells Constant the story of how he came to be on Mars and the circumstances of Bee's pregnancy and Chrono's birth. Constant, whose memory has been erased, does not realize that the story is about himself.

The Martian invasion is a joke. The forces are scattered over the globe and they are woefully under armed. They are slaughtered by the Earthlings, who begin to feel shameful for what they have done. Into this culture of shame, Rumfoord introduces his new religion.

Meanwhile on Mars, the ship takes off carrying only Boaz and Constant and a large supply of provisions. It has not been programmed to go to Earth, however. Instead it delivers them to the deep caves of Mercury, where they live in isolation for three years until Constant discovers the secret to tricking the ship's navigation system into flying him out of the caves. Boaz chooses to stay behind on Mercury, having found purpose in caring for the simple creatures that live in the caves.

Constant's ship returns him to Earth. He finds that he is expected. While he was in the caves in Mercury, Rumfoord has built up his new religion on Earth, one that teaches that God is indifferent to the fate of humankind, and that luck is not an actual force of nature or the hand of God. The religion also makes a negative example of Malachi Constant as a symbol of someone who imagined he had good luck and did nothing good with his fortune. Rumfoord has prophesied the return of Constant to Earth, calling him the Space Wanderer. Constant lands in a churchyard and is immediately hailed as the promised Space Wanderer. He is carried to the Rumfoord estate just as Rumfoord is about to materialize again.

Rumfoord has prepared a grand spectacle for the Space Wanderer and huge crowds await his arrival. Outside the estate, Bee and Chrono have become souvenir sellers catering to the religious crowd. Rumfoord brings Constant, Bee and Chrono together before the crowd and humiliates them revealing to all their true identities. He immediately instructs them to enter a spacecraft on a high column at the estate which will exile them, which they do. Before they go, Rumfoord deals one final blow to Constant by telling him the truth about the execution of Stony Stevenson, who Constant had hoped was still alive somewhere. It was Constant himself who killed Stony, Rumfoord tells him.

The three of them are flown in the ship to Titan, an inhabitable moon of Saturn. There they meet Rumfoord again, who is permanently materialized on Titan, where he has built a palace on a large sea. Titan is also inhabited by a creature named Salo, a machine whose ship has been marooned there for 200,000 years. Rumfoord reveals to them that all of human history has been directed by Salo's people on the planet Tralfamadore, who are able to cast their influence across vast distances. The primary purpose of this direction is to produce a single, small metal replacement part for Salo's space ship. This part has now been delivered. It is in the form of Chrono's good luck piece, a smooth scrap of metal he picked up as a child on Mars.

Rumfoord then disappears, the center of his existence having moved on to a different place in the universe. Salo, who has come to love Rumfoord, dismantles himself in sorrow. Beatrice moves into the palace, spending her last days writing. Chrono takes to the woods of Titan, going to live with the giant Titanic bluebirds that soar in the skies. There are no other humans on Titan. The beautiful women in the picture Rumfoord gave Constant at the beginning of the story turn out to be sculptures made by Salo as he whiled away the millennia waiting for the replacement part.

Constant lives peacefully on the land, occasionally visiting Beatrice in the palace. He reassembles Salo, who uses the replacement part to repair his ship. When Beatrice finally dies, Salo offers to return Constant to Earth. Constant accepts. Salo takes him to a bus stop in Indianapolis on a cold winter night. Before letting him go, Salo hypnotizes Constant so that when he is about to die he will imagine he is reunited with his friend Stony. Constant sits down in the bus stop and never gets up again. He freezes to death, but before he dies, he sees Stony coming to take him to paradise.