AbstractThe beneficial effects of icariin in the management of many diseases, such as chronic renal failure and heart failure, are well known. Icariin has also been shown to ameliorate osteoarthritis (OA) symptoms; however, the underlying mechanisms remain unclear. In this study, a bioinformatics analysis was performed to investigate the KEGG pathways of icariin‐targeted genes involved in OA. Our study suggests that icariin plays a role in OA by regulating inflammatory cytokine production, insulin resistance, and cell survival through modulation of the NF‐κB, MAPK, and Akt signaling pathways. Importantly, IKBKB, NFKBIA, MAPK8, MAPK9, and MAPK10 may be the hub genes affected by icariin when providing its beneficial effects on OA. In addition, we found that icariin decreases proinflammatory factors and inhibits chondrocyte apoptosis through suppression of the NF‐κB pathway. Our study highlights a set of KEGG pathways that could explain the molecular mechanism of icariin's action on OA, suggesting that icariin could be considered as a promising therapeutic option for OA.