Chronic heart failure (CHF) is the end stage of many severe heart diseases. Fuzi decoction (FZD) originates from Zhang Zhongjing's Treatise on Febrile Diseases and is widely used in the treatment of CHF in the clinic, but the potential mechanism of FZD in CHF is unclear. In this study, an integrated approach combining network pharmacology and metabolomics was adopted to explore the mechanism of FZD in CHF. Network pharmacological studies indicated that the most significant signaling pathway was the HIF-1 signaling pathway. Untargeted metabolomics indicated abnormalities in serum metabolism in CHF rats, and FZD treatment significantly improved the metabolic abnormalities and altered the levels of 30 metabolites. A pathway enrichment analysis showed that FZD was mainly involved in glycine, serine and threonine metabolism, aminoacyl-tRNA biosynthesis, β-alanine metabolism, pantothenate and CoA biosynthesis, glyoxylate and dicarboxylate metabolism and other metabolic pathways. A correlation analysis showed that pyruvate and lactate were strongly correlated with the heart failure index, and a targeted metabolomics study showed that FZD restored the balance of the pyruvate-lactate axis that was disrupted due to CHF. Therefore, the mechanism of FZD against CHF may be related to regulate HIF-1 signaling pathway, pyruvate-lactate axis and glycine, serine and threonine metabolism.