AbstractIn recent times, there has been growing attention towards exploring the nutritional and functional aspects of potato protein, along with its diverse applications. In the present study, we examined the anti‐osteoclast properties of potato protein hydrolysate (PP902) in vitro. Murine macrophages (RAW264.7) were differentiated into osteoclasts by receptor activator of nuclear factor‐κB ligand (RANKL), and PP902 was examined for its inhibitory effect. Initially, treatment with PP902 was found to significantly prevent RANKL‐induced morphological changes in macrophage cells, as determined by tartrate‐resistant acid phosphatase (TRAP) staining analysis. This notion was further supported by F‐actin analysis using a confocal microscope. Furthermore, PP902 treatment effectively and dose‐dependently down‐regulated the expression of RANKL‐induced osteoclastogenic marker genes, including TRAP, CTR, RANK, NFATc1, OC‐STAMP, and c‐Fos. These inhibitory effects were associated with suppressing NF‐κB transcriptional activation and subsequent reduced nuclear translocation. The decrease in NF‐κB activity resulted from reduced activation of its upstream kinases, including I‐κBα and IKKα. Moreover, PP902 significantly inhibited RANKL‐induced p38MAPK and ERK1/2 activities. Nevertheless, PP902 treatment prevents RANKL‐induced intracellular reactive oxygen species generation via increased HO‐1 activity. The combined antioxidant and anti‐inflammatory effects of PP902 resulted in significant suppression of osteoclastogenesis, suggesting its potential as an adjuvant therapy for osteoclast‐related diseases.