In 1926 New York, Newt Scamander arrives with a case full of magical creatures, but when some of them escape, he teams up with Tina and Jacob to capture them. Along the way, they uncover a dark force and must stop it before it wreaks havoc on the city. Newt also discovers a personal connection to a woman from his past.

In 1927, the dark wizard Gellert Grindelwald escapes custody and gathers followers to his cause. As the magical world becomes more divided, Newt Scamander and his friends set out to stop Grindelwald's plans to raise pure-blood wizards to rule over non-magical beings.

In Kweilin, China, 1932, Newt Scamander helps a Qilin - a magical creature that can see into one's soul as well as the future - give birth. Gellert Grindelwald's acolytes, led by Credence Barebone, attack and kill the mother and kidnap the newborn. Grindelwald subsequently kills the creature intending to harness its ability of precognition. However, unbeknownst to them, the Qilin had twins, the younger of which Newt saved. Unable to battle Grindelwald due to their blood pact, Albus Dumbledore recruits Newt, Newt's brother Theseus, Ilvermorny Charms teacher Lally Hicks, Senegalese-French wizard Yusuf Kama, American No-Maj Jacob Kowalski, and Newt's assistant Bunty Broadacre to thwart Grindelwald's plan for world domination. They travel to Berlin, Germany where Yusuf is planted as a spy in Grindelwald's inner circle. Grindelwald has his convert, Queenie Goldstein, use legilimency to test Yusuf's trustworthiness. The International Confederation of Wizards (ICW) acquits Grindelwald of all previous criminal charges, allowing for his candidacy as Supreme Mugwump of the ICW, despite Dumbledore's attempts to otherwise persuade current Supreme Mugwump Anton Vogel. Meanwhile, Grindelwald's acolytes, who have undermined the German Ministry of Magic, arrest Theseus and plot to assassinate the Brazilian Supreme Mugwump candidate, Vicência Santos. Dumbledore dispatches Newt to the Erkstag, the secret German wizarding prison, to find Theseus. Lally and Jacob successfully prevent the assassination. They escape but Jacob is framed for attempting to murder Grindelwald, who then justifies turning the Wizarding world against all Muggles. Meanwhile, Credence battles Albus Dumbledore, who quickly defeats him. Credence learns he is the illegitimate son of Aberforth Dumbledore, Albus Dumbledore's brother. Credence then questions his loyalty to Grindelwald. Elsewhere, Newt and Theseus escape the Erkstag and use a Portkey to transport to Hogwarts. Wizarding world leaders gather in Bhutan for the Walk of the Qilin ritual, where a Qilin selects a worthy new Supreme Mugwump. Grindelwald foresees Dumbledore and Newt smuggling the surviving twin Qilin to the ceremony in a suitcase. To thwart Grindelwald's cohorts, each Dumbledore ally carries an identical suitcase. As the team moves through the village, Queenie, who has renounced Grindelwald, finds and reunites with Jacob. Using necromancy, Grindelwald reanimates the dead Qilin and manipulates it to choose him during the Supreme Mugwump selection ceremony. Grindelwald immediately declares war on all Muggles and tortures Jacob. However, Credence, Newt, and Bunty expose him. Bunty produces the surviving Qilin which bows to Dumbledore, who declines the position. Santos is then chosen as the new Supreme Mugwump. Enraged, Grindelwald tries to kill Credence by casting the killing curse, but Credence is simultaneously protected by Aberforth (his father) and Albus (his uncle). Dumbledore's and Grindelwald's clashing spells break the blood pact. Their ensuing battle reaches a stalemate, and Grindelwald disapparates. In the aftermath, Aberforth accepts the ailing Credence as his son and takes him home. Jacob and Queenie marry at Jacob's bakery shop in New York City, with most of the group and Tina Goldstein in attendance. Newt spots Dumbledore watching from across the street. Dumbledore thanks Newt before disappearing into the night.