Annexins are well‐known Ca²⁺ phospholipid‐binding proteins, which have a wide variety of cellular functions. The role of annexin A1 (AnxA1) in the innate immune system has focused mainly on the anti‐inflammatory and proresolving properties through its binding to the formyl‐peptide receptor 2 (FPR2)/ALX receptor. However, studies suggesting an intracellular role of AnxA1 are emerging. In this study, we aimed to understand the role of AnxA1 for interleukin (IL)‐1β release in response to activators of the nucleotide‐binding domain leucine‐rich repeat (NLR) and pyrin domain containing receptor 3 (NLRP3) inflammasome. Using AnxA1 knockout mice, we observed that AnxA1 is required for IL‐1β release in vivo and in vitro. These effects were due to reduction of transcriptional levels of IL‐1β, NLRP3 and caspase‐1, a step called NLRP3 priming. Moreover, we demonstrate that AnxA1 co‐localize and directly bind to NLRP3, suggesting the role of AnxA1 in inflammasome activation is independent of its anti‐inflammatory role via FPR2. Therefore, AnxA1 regulates NLRP3 inflammasome priming and activation in a FPR2‐independent manner.