Bone homeostasis is maintained by the balance between osteoblastic bone formation and osteoclastic bone resorption. Hyperactive osteoclasts may lead to bone disorders including osteoporosis, osteolysis, and osteonecrosis of the femoral bead (ONFH). Growing evidence demonstrated that reactive oxygen species (ROS) mediate osteoclast formation and function. Herein, two novel small molecules, Helvolic Acid and Pseurotin A, were revealed to inhibit osteoclasts and ameliorate bone loss by suppressing ROS. Additionally, ROS were also involved in the progression of ONFH by enhancing osteoclast activity. Thus, these studies indicated that ROS may serve as anticatabolic targets for the osteoclast-related bone disorders.