Fructus Corni has been reported to contain a wide variety of pharmacological effects and previous studies had revealed that Fructus Corni might protect the cardiac indices. However, the all-encompassing metabolic profile of Fructus Corni has not been well illuminated. In this research, a high-sensitivity ultra-performance liquid chromatography with quadrupole time-of-flight mass spectrometry method was adopted to identify the metabolic profile after oral administration of Fructus Corni extract, especially the metabolic characterization of serum and heart, for which the targets and signaling pathways about heart failure were hunted through compound-target-disease-pathway intersection network. Ultimately, 37 ingredients were identified in Fructus Corni extract, and 22 prototypes and 134 metabolites that identified in serum, heart, feces and urine were tentatively characterized, which contained iridoids, flavonoids, tannins, organic acids and others. Additionally, 10 putative key compounds including 4 prototypes and 6 phase I metabolites were screened by network pharmacology and molecular docking, among which, secoxyloganin (P7), loganin (P14), cornuside Ⅲ (P17) and cornuside (P20) were the absorbed compounds to represent the potential active ingredients of Fructus Corni engaged in heart failure condition. In general, this method provided the combined strategy to preliminarily settle complex of Fructus Corni's metabolic profiling and anti-heart failure pharmacologic activities. This article is protected by copyright. All rights reserved.This article is protected by copyright. All rights reserved.