Background:Mycoplasma pneumoniae pneumonia (MPP) is a pulmonary inflammatory disease caused by Mycoplasma pneumoniae (Mp) infection that primarily involves the bronchi, alveoli, and pulmonary interstitium. It is the most common cause of community-acquired pneumonia in children. Andrographolide (AG) is a natural diterpenoid lactone with anti-inflammatory and immunomodulatory activities; however, its specific role and mechanism in MPP remain unclear. Objectives: This study aimed to investigate the mechanism by which AG inhibits pyroptosis in alveolar epithelial cells via the HMGB1/TLR4/NF-κB signaling pathway in the treatment of MPP in children. Methods: Mp-stimulated MLE-12 cells were treated with AG at 10, 20, or 50 μM. Cell viability and injury were assessed using CCK-8 and LDH assays, respectively. Protein expression levels of NLRP3, HMGB1, TLR4, and p-NF-κB p65 were determined by Western blotting, and cytokine levels (IL-6 and TNF-α) were measured by ELISA. In an Mp-infected mouse model, mice received AG at 25 or 50 mg/kg. Body weight, lung index, lung histopathology, pathway-related protein expression, and cytokine levels (IL-1β and TNF-α) in bronchoalveolar lavage fluid (BALF) were evaluated. Results: Mp significantly induced cytotoxicity, pyroptosis, and inflammation in vitro and in vivo (all P < 0.001). Andrographolide treatment dose-dependently reduced LDH release, suppressed HMGB1/TLR4/NF-κB/NLRP3 activation, and decreased proinflammatory cytokine levels (P < 0.05). In mice, AG improved survival-related metrics, ameliorated lung pathology, and inhibited pathway activity and cytokine secretion. Conclusions: Andrographolide mitigates MPP via the HMGB1/TLR4/NF-κB signaling pathway by inhibiting pulmonary epithelial cell pyroptosis and inflammation. These findings indicate its potential as a therapeutic agent.