In 1926, British wizard and magizoologist Newt Scamander arrives by boat to New York City en route to Arizona. He encounters Mary Lou Barebone, a non-magical woman ("No-Maj" or "Muggle") who heads the New Salem Philanthropic Society, which claims that witches and wizards are real and dangerous. As Newt listens to her speak, a Niffler escapes from his magically-expanded suitcase, which houses multiple magical creatures. As he attempts to capture it, he meets No-Maj cannery worker and aspiring baker, Jacob Kowalski and they accidentally swap suitcases. Demoted Auror (a hunter of dark wizards) Tina Goldstein arrests Newt for being an unregistered wizard and takes him to the Magical Congress of the United States of America (MACUSA) headquarters, hoping to regain her former position. However, as Jacob's suitcase contains only baked goods, Newt is released. At Jacob's tenement apartment, several creatures escape from Newt's suitcase. They destroy his apartment and one bites him.
After Tina and Newt find Jacob and the suitcase, Tina takes them to her apartment to be monitored for a few days, and introduces them to Queenie, her Legilimens sister. Queenie and Jacob are mutually attracted, though American wizards are forbidden to marry or even socially interact with No-Majs. Newt takes Jacob inside his magically-expanded suitcase where Jacob encounters a contained Obscurus, a dark, destructive parasite that lurks inside wizard children unable to control their magic. Newt extracted it from a young girl who has died, those afflicted rarely living past the age of ten. Newt persuades Jacob to help search for the missing creatures. After re-capturing two of the three escaped beasts, they re-enter the suitcase, which Tina takes to MACUSA. Officials arrest them, believing one of Newt's beasts is responsible for killing Senator Henry Shaw Jr. They decide to destroy Newt's suitcase and obliviate Jacob's recent memories. Director of Magical Security Percival Graves accuses Newt of conspiring with the infamous dark wizard Gellert Grindelwald. Newt and Tina are sentenced to immediate death, but Queenie and Jacob rescue them; the foursome then find and re-capture the last of the creatures.
Meanwhile, Percival Graves approaches Credence Barebone, Mary Lou's adopted teenage son, and offers to free him from his abusive mother. In exchange, he wants Credence to find an Obscurus. Graves believes it has caused the mysterious destructive incidents around the city. Credence finds a wand under his adopted-sister, Modesty's, bed. Mary Lou assumes it is Credence's wand, but Modesty claims it is hers. When she is about to be punished, the Obscurus is unleashed, killing everyone except Modesty and Credence. Graves arrives and dismisses Credence as being a Squib (a non-magical person of wizard ancestry), and refuses to teach him magic. Credence reveals he is the Obscurus' host, having lived longer than any other host due to the intensity of his magic. In a rage, he unleashes the Obscurus upon the city.
Newt finds Credence hiding in a subway tunnel, but he is attacked by Graves. Tina, who knows Credence, arrives and attempts to calm him, while Graves tries to convince Credence to listen to him. As Credence begins to settle into human form, Picquery and Aurors arrive. Picquery decides Credence must be executed to protect their magical society. The Aurors apparently disintegrate him, but a tiny Obscurus fragment escapes. Graves admits to unleashing the Obscurus to expose the magical community to the No-Majs, and angrily claims that MACUSA protects the No-Majs more than themselves. He is exposed as Gellert Grindelwald in disguise and taken into custody by MACUSA Aurors.
MACUSA fears their secret world has been exposed, but Newt releases his Thunderbird to disperse a poultice as rainfall over the city that erases all New Yorkers' recent memories as MACUSA wizards repair the destruction. Queenie kisses Jacob goodbye as the rain erases his memories. Newt departs for Europe, but promises to return and visit Tina when his book is finished; he also anonymously leaves Jacob a case of silver Occamy eggshells to fund his bakery. Jacob's bakery is a huge success, the fantastic shapes of his breads and pastries unknowingly inspired by Newt's beasts. Queenie visits the bakery, and Jacob notices her and it brings a huge smile to his face.