In 1926, Newt Scamander arrives at the Magical Congress of the United States of America with a magically expanded briefcase, which houses a number of dangerous creatures and their habitats. When the creatures escape from the briefcase, it sends the American wizarding authorities after Newt, and threatens to strain even further the state of magical and non-magical relations.

In a universe where humans are near the bottom of the evolutionary ladder, a young destitute human woman is targeted for assassination by the Queen of the Universe because her very existence threatens to end the Queen's reign.