Pseudomonas aeruginosa is a widely distributed Gram-negative opportunistic pathogen that poses a serious threat to immunocompromised individuals, often leading to severe clinical infections. Sodium houttuyfonate (SH), the main active derivative of the Chinese medicinal herb Houttuynia cordata, has been widely used for anti-infection therapy. Recent studies suggest that the efficacy of SH against antibiotic-resistant pathogens extends beyond direct antibacterial effects to include delicate regulation of the host immune system. [Objective] To investigate the role of SH in promoting M1 polarization of alveolar macrophages against P. aeruginosa infection. [Methods] A mouse model of acute pneumonia caused by P. aeruginosa was established via intratracheal intubation. Hematoxylin and eosin (HE) staining was used to evaluate the histopathological changes in the lung tissue. Bacterial load in the lung tissue was determined by the plate counting method, and the expression of Toll-like receptor 4 (TLR-4) in the lung tissue was analyzed by immunohistochemistry (IHC). In the cell experiment, MH-S alveolar macrophages were co-cultured with SH for 6 h to induce M1 polarization. Polarization markers CD86 and CD206 were analyzed by immunofluorescence and flow cytometry, and phagocytic capacity was evaluated with P. aeruginosa at 1×10⁵ CFU/mL. The mRNA levels and inflammation levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and interleukin-10 (IL-10) were measured by RT-qPCR and ELISA, respectively. The expression of proteins in the TLR-4/MyD88/NF-κB signaling pathway was analyzed by Western blotting. To decipher the mechanism, we constructed TLR-4 overexpression and knockdown cell models to confirm SH regulation of this pathway and related inflammatory factors via TLR-4. [Results] The in vivo experiment results indicated that SH significantly reduced P. aeruginosa proliferation in the mouse lung tissue. Both HE staining and IHC results demonstrated that pulmonary inflammation in the treatment group was alleviated compared with the model group, suggesting that SH may enhance host immune clearance and thereby mitigate acute pulmonary infection. The cell experiment showed that SH promoted early M1 polarization of MH-S cells and enhanced their phagocytosis of P. aeruginosa. Western blotting further confirmed activation of the TLR-4/MyD88/NF-κB pathway with upregulated protein expression after SH treatment. [Conclusion] SH can activate the TLR-4/MyD88/NF-κB pathway to induce M1 polarization of alveolar macrophages during early infection, thereby exerting significant phagocytic and anti-infective effects.