Objective Based on the method of network pharmacology, the mechanism of Angelicae Pubescentis Radix-Notopterygii Rhizoma et Radix-Asari Radix et Rhizoma in the treatment of knee osteoarthritis was analyzed and predicted. Methods The TCMSP database was used to obtain the active ingredients and targets of Angelicae Pubescentis Radix-Notopterygii Rhizoma et Radix-Asari Radix et Rhizoma, and the gene targets of knee osteoarthritis obtained from CTD, NCBI and other databases were mapped to build a drug-active ingredient-disease target network. MCODE cluster analysis was carried out, and GO and KEGG pathway enrichment analysis was carried out through Omicshare cloud platform and DAVID database. Results A total of 36 active ingredients and 205 targets were screened from the three medicines. The key active compounds included kaempferol, β-sitosterol, sesamin, marmesinin and so on, the key targets included AKT1, ESR1, JUN, CASP3, etc. NOS3, ESR1, ACOX1 and NR1I2 are core genes. Steroid hormone responsiveness, reactive oxygen species metabolism, AGE-RAGE pathway and TNF pathway are the key biological processes and pathways. Conclusion Angelicae Pubescentis Radix, Notopterygii Rhizoma et Radix, Asari Radix et Rhizoma may treat knee osteoarthritis through multi-component and multi-target network.