Activation of the NLRP3 inflammasome and estrogen receptor alpha (ERalpha) has been shown to increase the risk of inflammatory bowel diseases (IBD) or promote disease recurrence. In previous work, we demonstrated that ERalpha regulated the transcription of NLRP3. However, the precise mechanism by which ERalpha modulates NLRP3 in IBD models remains unclear. In this study, we induced IBD in wild-type mice using DSS or TNBS, followed by treatment with the ERalpha-specific agonist PPT. The results showed that IBD symptoms and intestinal inflammation responses were significantly exacerbated after PPT treatment. Furthermore, the activation of ERalpha by PPT led to a marked increase in the expression of NLRP3 and pro-inflammatory cytokines, including IL-1beta and IL-18, suggesting that ERalpha activation exacerbated intestinal inflammation and impaired mucosal healing during the recovery phase of inflammation. In contrast, ERalpha-knockout mice exhibited only mild symptoms when exposed to DSS or TNBS, with a concurrent reduction in NLRP3 expression, indicating that ERalpha plays a role in inflammation susceptibility. Similar findings were observed in NCM-460 cells, where the inflammation response was attenuated in ERalpha-knockdown cells. Importantly, we demonstrated that ERalpha interacted with the NLRP3 inflammasome and promoted its assembly. Collectively, we propose an underlying pathogenesis of IBD, that is, ERalpha can interact with the NLRP3 inflammasome and promote its expression and assembly, thereby exacerbating intestinal inflammation in IBD models. Therefore, ERalpha could serve as a potential therapeutic target for NLRP3 inflammasome-associated intestinal inflammation.