Osteonecrosis of the jaw (ONJ) is associated with the use of bisphosphonates (BPs), denosumab, and antiangiogenic drugs; however, the pathophysiology of medication-related ONJ (MRONJ) remains unknown. Recent advances in therapies for diseases that affect bone remodeling have led to the development of agents that inhibit the receptor activator of nuclear factor-kappa B ligand (RANKL). One such inhibitor is denosumab, a highly specific, fully human immunoglobulin G2 monoclonal antibody against RANKL. We report a case of ONJ that developed following dental extraction in a patient treated for metastatic colorectal cancer with denosumab. At the first medical examination at our hospital, her clinical presentation was indistinguishable from stage 2 MRONJ, classified according to the 2014 American Academy of Oral Medicine position paper. Discontinuation of denosumab was directed by her oncologist, and we prescribed oral antibiotics and irrigated the exposed area of bone. Seven months after denosumab cessation, the sequestrum of the anterior part of the mandible was naturally shed and the site was healed. Denosumab and BPs have significantly different mechanisms of action. The effects of denosumab on bone turnover are more rapid and reversible than those of BPs. Discontinuation of denosumab may be effective in the management of denosumab-related ONJ, depending on the primary tumor control.