<p>Granulomatous lobular mastitis (GLM) is a chronic, refractory inflammatory condition of the breast with an unclear etiology. Emerging evidence suggests a potential role of pyroptosis in the pathogenesis of GLM. This study investigated the therapeutic effects of Tuolitounong Decoction (TLTND) on pyroptosis in both in vitro and in vivo models of GLM. An in vitro GLM model was established using MCF10A mammary epithelial cells exposed to tissue homogenates derived from GLM-affected human breast tissue. Cells were treated with TLTND at varying concentrations, with or without the pyroptosis inhibitor necrosulfonamide. Pyroptosis-associated proteins, including caspase-1, gasdermin D (GSDMD), lipopolysaccharide-binding protein (LBP), and NLR family pyrin domain containing 3 (NLRP3), were assessed using immunofluorescence and western blotting. Cell viability was evaluated using the Cell Counting Kit-8 (CCK-8) assay. For in vivo analysis, a rat GLM model was induced by injecting a combination of human GLM tissue homogenate supernatant and Freund’s complete adjuvant into the third and fourth pairs of mammary glands in female Sprague Dawley rats. TLTND was administered via daily oral gavage for 21 days. Post-treatment evaluations included histopathological assessment, expression of estrogen receptor (ER) and progesterone receptor (PR), and pyroptosis-related biomarkers in mammary gland tissue. Exposure to GLM homogenate successfully induced pyroptosis-related pathological features in MCF10A cells, whereas serotonin (5-HT) inhibition showed no significant effect. TLTND treatment demonstrated dose- and time-dependent effects, with enhanced therapeutic efficacy at 10 mg/mL after 48 h (<i>P</i> = 0.009). Of note, TLTND significantly reduced the protein expression levels of key pyroptosis markers (cleaved caspase-1, n-GSDMD, cleaved IL-18 and cleaved IL-1β) by 52.6%, 91.0%, 78.1% and 87.1%, respectively, compared to the model group in rat mammary tissue. Co-treatment with TLTND and necrosulfonamide significantly downregulated the expression of caspase-1, GSDMD, LBP, and NLRP3, while increasing cell viability. In vivo, both prednisone acetate and TLTND ameliorated histopathological features of GLM. Notably, TLTND promoted localized abscess maturation and increased ER and PR expression, while reducing levels of interleukin-1β and GSDMD-N in mammary tissue. TLTND demonstrated therapeutic potential in reducing pyroptosis in mammary epithelial cells and modulating inflammation in granulomatous lobular mastitis, partly by downregulating the caspase-1/GSDMD-mediated pyroptosis signaling pathway. These findings support further investigation of TLTND as a complementary treatment approach for GLM and provide insight into its underlying mechanisms of action.</p>