Newspaper illustrator John Moore meets with criminal psychologist (alienist) Dr. Laszlo Kreizler to investigate a serial killer in New York during the late 19th century.

The Alienist opens when a series of haunting, gruesome murders of boy prostitutes grips New York City. Newly appointed police commissioner Theodore Roosevelt (Geraghty) calls upon criminal psychologist (aka alienist) Dr. Laszlo Kreizler (Brühl) and newspaper illustrator John Moore (Evans) to conduct the investigation in secret.

They are joined by Sara Howard (Fanning), a headstrong secretary determined to become the city's first female police detective. Using the emerging disciplines of psychology and early forensic investigation techniques, this band of social outsiders set out to find and apprehend one of New York City's first serial killers.