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Background: Cancer cachexia is a complex disease secondary to cancer, and no specific therapy for it has been found. The Chinese herb Kushen (Radix Sophorae flavescentis) is the dried root of Sophora flavescens Aiton, which has been widely applied in treating digestive and urinary inflammatory diseases. Matrine, one of the main components of Radix Sophorae flavescentis, can alleviate cancer cachexia. Methods: Compounds from Radix Sophorae flavescentis were screened using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform. The targets related to cancer cachexia were queried from the Therapeutic Target Database (http://db.idrblab.net), DisGeNET database (http://www.disgenet.org), and Search Tool for Interacting Chemicals database, related literature, and constructed cancer cachexia-protein network. Cancer cachexia-protein network was merged with compound-protein networks respectively using Cytoscape software as well as network topology data and key targets counting. Pathway enrichment analysis was conducted via the Database for Functional Annotation Bioinformatics Microarray Analysis. Protein crystal structures and compound structures were queried from RCSB and PubChem databases, respectively. Molecular docking was conducted using Discovery Studio software. Results:The anticancer cachexia compounds of Radix Sophorae flavescentis were screened as oxymatrine, matrine, and kurarinol, and targets such as BIRC2, TNF and STAT3 were found. The mechanisms of oxymatrine, matrine, and kurarinol have the characteristics of synergy and complementarity. Kurarinol has a mechanism similar to that of matrine, which includes the FoxO signaling pathway, insulin resistance and mTOR signaling pathway. TNF signaling pathway is a common signaling pathway of kurarinol, oxymatrine and matrine. Adipocytokine signaling pathway is the other common pathway of kurarinol and oxymatrine except for the TNF signaling pathway. Kurarinol can be successfully docked with CYCS, GPX2, BIRC7, etc., and kushenol C can be successfully docked with IKBKB and PIK3CD. Conclusion: Kurarinol, matrine, oxymatrine, and kushenol C may be the key compounds of Radix Sophorae flavescentis treating cancer cachexia. Additionally, TNF signaling pathway is the key pathway for the synergistic action of kurarinol, matrine and oxymatrine.