After years of personal and professional turmoil, things are finally looking up for Columbus, Ohio, private eye Andy Hayes. As Sick to Death opens, Andy is relishing his new gig: a drama-free, family-friendly stint as a guard at the Columbus Museum of Art. What could be better than regular hours, a steady paycheck, and an attractive coworker who may be just as interested in him as he is in her? Right on schedule, Andy's newfound equilibrium comes crashing down when he interrupts the theft of a painting by famed Ashcan school realist George Bellows--and is promptly fired for breaking museum protocols. Helping him thwart the robbers is a young woman whom Andy has caught staring at him several times at the museum. To his shock, she reveals she's an adult daughter he never knew he had, the result of a one-night stand during his misspent youth a quarter century earlier. But Alex Rutledge, about to enter the Columbus Police Academy, isn't looking for family time. She wants to hire her newly discovered father to find the driver who killed her mother, Kate, five months earlier in a still unsolved hit-skip accident. Even as Andy reels from this personal development, he uncovers troubling details about Kate's death that increasingly point toward murder and an angry anti-vax sentiment roiling below the surface at the hospital where she worked.

Complicating Andy's case, he finds himself in the crosshairs of an FBI investigation into the attempted art theft. With time running out and his and Alex's lives on the line, Andy rushes to defend his reputation as a private eye and find Kate's killer.