Objective To investigate the effect of gastrodin (GAS) on inflammatory injury and the AMPdependent protein kinase / nuclear factor κB/ nucleotide-binding oligomerization domain-like receptor protein 3 (AMPK/ NF-κB/ NLRP3) pathway in rats with periodontitis. Methods A periodontitis rats model was constructed,and successfully modeled rats were randomly assigned into either the Model group, low, medium, and high-dose GAS (GAS-L, GAS-M, and GAS-H, respectively), or high-dose GAS+pathway inhibitor compound C group (GAS-H+CC), with 18 rats in each. Additionally, 18 healthy normal rats formed the Control group. The gingival index and the gingival bleeding index of rats were evaluated. Microscopic computed tomography was used to measure alveolar bone resorption, cemento-enamel junction-alveolar bone crest (CEJ-ABC) distance, and bone mineral density. Enzymelinked immunosorbent assay was used to detect levels of inflammatory factors in serum and periodontal tissues.Hematoxylin-eosin staining was performed to detect pathological damage in periodontal tissue. Tartrate-resistant acid phosphatase staining was performed to detect the number of osteoclasts in periodontal tissue. Immunohistochemical detection of the expression of bone metabolism-related proteins in periodontal tissues was performed, and Western blot was used to detect the expression of AMPK/ NF-κB/ NLRP3 pathway-related proteins. Results Compared with the Model group, the GAS-L, GAS-M, and GAS-H groups showed reduced periodontal tissue pathological damage, bone resorption cavities, inflammatory cell infiltration, gingival index, gingival bleeding index, CEJ-ABC distance, tumor necrosis factor (TNF)-α, interleukin (IL)-6, tissue damage score, osteoclast count, RANKL, p-NF-κB p65 / NF-κB p65, and NLRP3, while bone mineral density, osteoprotegerin (OPG), osteocalcin (OCN), and p-AMPK/ AMPK increased (P<0. 05,P<0. 01). The GAS-H+CC group showed more severe periodontal tissue pathological damage than the GAS-H group; the gingival index, gingival bleeding index, CEJ-ABC distance, TNF-α, IL-6, tissue damage score, osteoclast count, RANKL, p-NF-κB p65 / NF-κB p65, and NLRP3 increased, while bone mineral density,OPG, OCN, and p-AMPK/ AMPK decreased (P<0. 05,P<0. 01). Conclusions GAS improved inflammatory injury in periodontitis rats through regulating the AMPK/ NF-κB/ NLRP3 pathway.