Wearing titanium particle‐induced osteoclastogenesis, accompanied by peri‐implant osteolysis, is the main cause of long‐term failure of hip prosthesis. Currently, medications used for the prevention and treatment of peri‐implant osteolysis show serious side effects. Therefore, development for more effective new drugs with less side effects is extremely urgent. Vaccarin is a natural flavonoid extracted from Vaccaria segetalis, with various biological functions, including antioxidantory, anti‐inflammatory, and promotion of angiogenesis. However, the putative role of vaccarin in the inhibition of titanium particle‐induced osteolysis has not been reported. In this study, it was indicated that vaccarin could effectively inhibit RANKL‐induced osteoclastogenesis, fusion of F‐actin rings, bone resorption, and expression of osteoclast marker genes in a dose‐dependent manner in vitro. Moreover, vaccarin could also inhibit RANKL‐induced osteoclastogenesis via the inhibition of NF‐κB and MAPK (p38, ERK, and JNK) signaling pathways, and inhibit the transcription of downstream transcription factors, such as c‐Fos and NFATc1. Consistent with in vitro results, this in vivo study showed that vaccarin exhibited an inhibitory effect on titanium particle‐induced osteolysis by antiosteoclastogenesis. In conclusion, vaccarin could be a promising agent for preventing and treating peri‐implant osteolysis. This is a very valuable study. Vaccarin (Vac) could inhibit osteoclast formation and function, and titanium (Ti) particle‐induced osteolysis both in vivo and in vitro. This effect may be associated with the inhibition of RANKL‐mediated of NF‐κB and MAPK (p38, ERK, and JNK) signaling pathways. Thus, Vac may provide an alternative prevention and treatment approach for peri‐implant osteolysis caused by Ti particles.