Shengxian Quyu decoction (SXQY) has been suggested as a potential therapeutic strategy for heart failure (HF), but its therapeutic mechanisms remain unclear. This study investigated the therapeutic effects and underlying mechanisms of SXQY in HF. A rat model of HF was induced by transverse aortic constriction (TAC) and treated with SXQY. Cardiac function was assessed by transthoracic echocardiography, and myocardial structure and fibrosis were evaluated using hematoxylin and eosin and Masson's trichrome staining. Serum samples were analyzed by untargeted metabolomics using ultra-performance liquid chromatography-tandem mass spectrometry. Blood-entering components were mapped to targets, and intersecting HF-related targets were analyzed using protein-protein interaction (PPI) network analysis, followed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. SXQY significantly improved cardiac function in TAC rats, as evidenced by decreased left ventricular internal diameter in diastole and left ventricular posterior wall thickness in diastole and increased left ventricular ejection fraction, and alleviated myocardial hypertrophy, inflammation, and fibrosis. A total of 563 blood-entry compounds were identified (367 prototypes and 196 metabolites), with 5 key active compounds identified in the Traditional Chinese Medicine Systems Pharmacology database corresponding to 63 targets. Network analysis revealed 44 overlapping genes, with Formononetin, Timosaponin BII, and Sinensetin as core components, and PTGS2, PPARG, and HSP90AA1 as hub targets. PPI analysis further identified key genes including ESR1, PTGS2, PPARG, HSP90AA1, JUN, and 15 additional genes. KEGG analysis indicated that SXQY mainly acts via Ca2+, phosphatidylinositol 3-kinase-protein kinase B, cyclic adenosine monophosphate, and inflammation- and hormone-related pathways. In conclusion, SXQY exerts protective effects against HF by improving cardiac function and attenuating myocardial remodeling through multicomponent, multitarget, and multipathway mechanisms.