INTRODUCTION: Chronic Obstructive Pulmonary Disease (COPD) is a chronic inflammatory disorder characterized by irreversible airflow limitation and systemic immune impacts. COPD patients demonstrate an increased susceptibility to sepsis and septic shock, underscoring the importance of understanding its effects on splenic function. METHODS: A rat COPD model was established using lipopolysaccharide (LPS) and cigarette smoke exposure. Splenic function was assessed through carbon clearance assays, histological analysis, and high-throughput mRNA sequencing. In vitro assays were conducted to evaluate the role of secretoglobin family 1a member 1 (SCGB1A1) in macrophage activation and lymphocyte proliferation. RESULTS: Carbon clearance assays revealed a significant reduction in splenic phagocytic activity in the smoke-exposed group. Histological analysis showed lymphoid follicle atrophy and connective tissue hyperplasia. High-throughput mRNA sequencing identified 102 upregulated and 32 downregulated genes in the smoke-exposed group, with SCGB1A1 notably upregulated. In vitro assays confirmed that SCGB1A1 inhibits LPS-induced macrophage activation and Phytohemagglutinin (PHA)-induced lymphocyte proliferation. CONCLUSION: These findings suggest that SCGB1A1 contributes to splenic immune dysfunction in COPD. Targeted inhibition of SCGB1A1 expression in the spleen may represent a potential therapeutic strategy to reduce the risk of sepsis in COPD patients.