AIM: To investigate the protective effect of sinomenine hydrochloride (SIN) on adjuvant arthritis (AA) rats by regulating the NLRP3/Gasdermin D/Caspase-1/Interleukin-1β pyroptosis pathway. METHODS: Sixty rats were randomly divided into 6 groups, 10 rats in each group: Con group (normal rats), AA group (AA rat model), L-SIN group (AA rats were intragastrically administered with 100 mg/kg SIN), M-SIN group (AA rats were intragastrically administered with 200 mg/kg SIN), H-SIN group (AA rats were intragastrically administered with 400 mg/kg SIN), ACG group (positive drug group: AA rats were intragastrically administered with 150 mg/kg Wantong Jingu Tablets). Observe the degree of joint swelling and arthritis index. HE was used to observe the pathological changes of the right ankle joint tissue of rats. The levels of inflammatory factors and oxidative stress-related indicators in synovial tissue were detected. Western Blot was used to detect the expression levels of NLRP3/Gasdermin D/Caspase-1/Interleukin-1β pyroptosis pathway-related proteins. RESULTS: Compared with Con group, the degree of joint swelling, arthritis index, inflammatory factors and oxidative stress levels, NLRP3, GSDMD, Caspase-1 and IL-1β protein expression levels in AA group were significantly increased (P<0.05). Compared with AA group, the degree of joint swelling, arthritis index, inflammatory factors and oxidative stress levels, NLRP3, GSDMD, Caspase-1 and IL-1β protein expression levels were significantly decreased in SIN treatment group with the increase of treatment dose (P<0.05). Compared with AA group and L-SIN group, the degree of joint swelling, arthritis index, inflammatory factors and oxidative stress levels, NLRP3, GSDMD, Caspase-1 and IL-1β protein expression levels in ACG group were significantly decreased (P<0.05). Compared with H-SIN group, the degree of joint swelling, arthritis index, inflammatory factors and oxidative stress levels, NLRP3, GSDMD, Caspase-1 and IL-1β protein expression levels in ACG group were significantly increased (P<0.05). CONCLUSION: SIN can alleviate the inflammatory injury of AA rats and reduce the levels of inflammatory factors and oxidative stress, thus exerting a protective effect on AA rats. The mechanism may be based on the NLRP3/Gasdermin D/Caspase-1/Interleukin-1β pyroptosis pathway.