Echopraxia follows the story of a biologist who gets caught up in a voyage into the heart of the Solar System among members of a transcendentalist monastic order and allies (including a vampire escaped from a research facility and her cadre of zombified soldiers) to investigate a mysterious signal seemingly coming from the mission sent to initiate first contact in Watts' previous novel.

The story, set on the eve of the twenty-second century, follows a parasitologist named Daniel Brüks, who accidentally finds himself trapped within a conflict involving several trans-human groups.

Forced to escape into space, he boards the starship Crown Of Thorns, together with a varied crew that includes Valerie, a vampire; Lianna Lutterodt, a monastic apprentice; Jim Moore, a soldier; Rakshi Sengupta, the pilot; and the Bicamerals, a group of trans-humans able to share thoughts and brainpower without the need for verbal communication.

During the trip, several secondary plot points are explored: the relationship between Brüks and his ex-wife, Rho, who decided to ascend to "Heaven", a custom virtual reality world for people who don't want to go on with their ordinary lives; the relationship between Jim Moore and his son, Siri Keeton, who travelled on the Theseus several years ago; Sengupta's search for the man who caused her wife's death; and Valerie's escape from the neurological chains that her human creators had imposed on her.

Echopraxia explores topics like the nature of consciousness and the actual need (or lack) for it in evolved creatures, the use of religion to advance knowledge beyond science, the existence of God as a virus that modifies the laws of physics, and the role that baseline (non-modified) humans can have in a society where everyone else is "augmented" in one way or another.