Hepatopulmonary syndrome (HPS) is a condition characterized by pulmonary angiogenesis and refractory hypoxemia, often seen in patients with chronic liver disease. Its unclear mechanism means that liver transplantation is the only effective therapy. Agrimoniin, a compound from Pilosa ledeb, shows potential in protecting against liver cirrhosis via anti-angiogenic and anti-glycolytic effects. This study investigates agrimoniin as a potential integrated therapy for HPS-related liver and lung dysfunction. Using transcriptome data and an ICU cohort, we analyzed the role of glycolysis in chronic liver disease progression. HPS rats were established via common bile duct ligation, and serum metabolites were measured. The oxygen consumption rate and extracellular acidification rate were also detected. Rats were treated with agrimoniin (3 mg/kg/day or 8 mg/kg/day) at the early stage of HPS. Our results showed that imbalanced oxidative phosphorylation and glycolysis correlated with chronic liver disease progression and poorer outcomes. Decreased oxygen consumption rate and increased extracellular acidification rate, as well as increased glycolysis, were observed in the HPS group. Agrimoniin treatment improved liver and lung function by inhibiting pathological angiogenesis and glycolysis. Through TCM suite analysis, molecular docking, and dynamics simulations, PGC-1α was identified as a potential target of agrimoniin. Inhibiting PGC-1α blocked agrimoniin's benefits on angiogenesis and glycolysis flux. Thus, agrimoniin may be a potential integrated therapy for HPS by activating PGC-1α to inhibit glycolysis and angiogenesis.