The 49th ceremony of the Annie Awards, honoring excellence in the field of animation for the year of 2021, was held on March 12, 2022, at the University of California, Los Angeles's Royce Hall in Los Angeles, California as a virtual event. The nominations were announced on December 21, 2021.

The nominees were announced on December 21, 2021, Raya and the Last Dragon led the nominations with ten, followed by Encanto with nine. For TV, Arcane led with nine nominations, followed by Maya and the Three with seven.

Belle received five Annie Award nominations, including one for Best Independent Animated Feature. It was the most nominated Japanese anime film at the awards until both The Boy and The Heron and Suzume surpassed it with 7 nominations two years later.

The Mitchells vs. the Machines (Film) and Arcane (TV) have swept every awards of its nominations with eight and nine, became the first year to sweep both. The Mitchells vs. the Machines became the second film by Sony Pictures Animation to sweep the Annies after Spider-Man: Into the Spider-Verse in 2019. Arcane became the first television series to both win the most awards in a single year and season, and to sweep the Annies. Flee also won Best Animated Feature — Independent, making it the first animated documentary to do so.

Winners are highlighted in boldface