Objective: To investigate the efficacy and mechanism of Mahuang Lianqiao Chixiaodou decoction (MLCD) in intervening in the “internal and external crosstalk” between skin barrier dysfunction and immune inflammation in an atopic dermatitis-like (AD-like) mouse model via the NOD-like receptor protein 3 (NLRP3) pyroptosis pathway. Methods: AD-like model mice were induced with 2,4-dinitrofluorobenzene and treated with MLCD or mometasone furoate gel (MF, positive control) for 7 days. Pathological changes in skin tissue were examined using Masson or methamphetamine blue staining. A smart skin analyzer, flow cytometry, fluorescence quantitative polymerase chain reaction, and western blotting were used to observe and evaluate skin barrier dysfunction, immune inflammatory responses, and skin cell pyroptosis in AD-like mice. Results: MLCD and MF improved skin damage and reduced pathological tissue damage and mast cell infiltration in AD-like mice to varying degrees. MLCD significantly reduced skin pigmentation and inflammatory status (P = .005 and P = .038, respectively), increased the percentage of splenic CD4+CD3+ T cells (P = .022), decreased the CD8+CD3+ T cell percentage (P = .044), decreased the CD8+CD3+/CD3+ ratio (P = .031) and increased the CD4+CD3+/CD8+CD3+ ratio (P = .027). MLCD also significantly decreased the mRNA expression levels of cell scorch-related factors NLRP3, casp-1, interleukin (IL)-1β, and IL-18 (P = .027, P
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