A Discovery of Witches is the first novel in Deborah Harkness' All Souls Trilogy. Primarily taking place at Oxford University, the story centers around a witch named Diana Bishop who has rejected her heritage and magic due to her parent's deaths early in her life. While preparing a speech in the library, Diana discovers a book of magic called Ashmole 782. Upon opening it, she unknowingly summons witches, demons, and other creatures to her location.

Creatures disguised as humans begin to monitor Diana, one being the vampire Matthew Clairmont. Matthew has spent his long life looking for Ashmole 782 and believes that it contains the secret for the survival of magical species. He begins to woo Diane in order to get closer to the book.

Diana begins to receive threats in regard to the book. A witch named Gillian tells her that her parents were killed by other witches for their secrecy. Frightened, Diana tells Matthew about the book and asks for his help. Matthew confesses that he is 1,500 years old and has been concerned about the races of witches and vampires dying out.

The two begin to fall in love, but it is revealed through Matthew's son that there is a organization called the Congregation that has outlawed love between different magical creatures. It is also revealed through a blood test meant to measure Diana's magical prowess that only she can open Ashmole 782.

Matthew attempts to protect Diana by hiding her at his mother's French estate, but she is kidnapped by a witch named Satu who craves her magical secrets. Matthew and his companions free Diana and hide her in New York at her Aunt Sarah's home, where Diana learns from a missing page of Ashmole 782 that she could bear a vampire's son. She also finds a note from her mother about a special ability passed to her known as "timewalking."

Matthew is attacked by a vampire sent by the Congregation. In order to safely study Ashmole 782, Diana and Matthew timewalk to 1500s London, where they begin their work.