Objective  To investigate the protective effect of microRNA-21-5p on lipopolysaccharide (LPS)-induced acute pulpitis (AP) in rats via the Nod-like receptor pyrin domain-containing (NLRP3)/cysteine aspartate 1 (CASP1) signaling pathway.  Methods  Forty SD rats were randomly divided into four groups, including control group (CON), AP model group (AP), AP+miR-21-5p negative control group (AP+ NC), and AP+miR-21-5p agomir group (AP+ agomir), n=10 per group. The AP model was established by opening the pulp chamber of molars and locally applying LPS (10 g/L). The AP+ agomir group received local injections of miR-21-5p agomir (5 μmol/ L) on day 1 and 2 after modeling. On the third day after model construction, rats were euthanized. Histopathological changes in the pulp were observed via HE staining and Masson staining. Fluorescence in situ hybridization (FISH) combined with immunofluorescence was used to detect miR-21-5p expression. Real-time PCR measured mRNA levels of miR-21-5p, tumor necrosis factor α (TNF-α), interleukin (IL)-6, and IL-1β. Western blotting assessed NLRP3 and CASP1 protein expression. Immunohistochemistry examined the expression of IL-6, IL-1β, and TNF-α-positive cells. RNA sequencing (RNA-seq) analyzed differentially expressed genes.   Results  Compared with the CON group, the AP group exhibited significantly increased inflammatory cell infiltration, elevated expression of pro-inflammatory factors (IL-6, IL-1β, and TNF-α), and decreased expression of miR-21-5p. Agomir targeting miR-21-5p significantly reduced inflammatory infiltration, promoted collagen fiber formation and reparative dentin formation, and downregulated the expression of NLRP3 and CASP1 proteins. RNA sequencing revealed that the NLRP3 inflammasome pathway was significantly inhibited.   Conclusion  MiR-21-5p alleviates LPS-induced dental pulp inflammation by inhibiting the activation of the NLRP3/CASP1 pathway.