Ryland Grace, PhD is the main protagonist of Project Hail Mary, portrayed by Ryan Gosling. A self-deprecating 8th grade science teacher, Grace was shunned from higher education and became the laughing stock of his scientific peers after releasing a paper on why water lacks importance for evolution. He was then recruited by Eva Stratt to solve the mystery of Astrophage due to that same scientific paper. His brilliance and knowledge on Astrophage makes him an unwilling member of the Hail Mary space expedition, where he's placed into a medically induced coma for four years. He awakens with no memory of his life, his cohorts are dead, and the only life form he encounters is an alien he calls Rocky.

Simon, commonly referred to as “the Convict," was formerly a Brother of Eden before being captured by the Consolidation of Iron following the destruction of Filament Station. After surrendering to the C.O.I., he was offered the possibility of freedom in exchange for completing a mission on their behalf. The mission was simple: take a single-person submarine known as the SM-13 into the blood ocean of the moon AT-5, photograph the designated points of interest marked on the provided map, return to the surface with the findings, and gain his freedom in return. After securing and protecting the Black Box, he is drowned and crushed to death by the Monster, but not before the sapling pendant he was holding was mutated by the blood, with its sudden, rapid growth destroying the SM-13 and taking it with him.

Rocky is an Eridian engineer from the planet Erid in the 40 Eridani solar system. He was sent to Tau Ceti with twenty-two other Eridian scientists/crewmates to save their star and planet from Astrophage. As an Eridian, he has no facial features and no sense of sight, instead using hearing and echolocation as his primary sense. He communicates using musical tones and chords. Rocky's true name in the Eridian language is a series of musical chords, but Grace calls him "Rocky" for his rock-like appearance.