BACKGROUND Cornus officinalis (CO), also known as 'Shanzhuyu', is one of the most common traditional Chinese herbs used against osteoporosis. Although previous studies have found that CO has beneficial effects in alleviating osteoporosis, its mechanisms remain unclear. MATERIAL AND METHODS In this study, we applied system bioinformatic approaches to investigate the possible therapeutic mechanisms of CO against osteoporosis. We collected the active ingredients of CO and their targets from the TCMSP, BATMAN-TCM, and ETCM databases. Next, we obtained the osteoporosis targets from differentially expressed mRNAs from the Gene Expression Omnibus (GEO) gene series (GSE35958). Next, the shared genes of the CO pharmacological targets and osteoporosis-related targets were selected to construct the protein-protein interaction network, based on the results from the STRING database. Subsequently, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were carried out by using the clusterProfiler package in R software. RESULTS In all, there were 58 unique CO compounds and 518 therapeutic targets. Based on the GO and KEGG enrichment results of 98 common genes, we selected the top 25 terms, based on the terms' P values. We found that the anti-osteoporotic effect of CO may mostly involve the regulation of calcium metabolism and reactive oxygen species, and the estrogen signaling pathway and osteoclast differentiation pathway. CONCLUSIONS We found the possible mechanisms of CO in treating osteoporosis may be based on multiple targets and pathways. We also provided a theoretical basis and promising direction for investigating the exact anti-osteoporotic mechanisms of CO.