The designation of immune checkpoint inhibitors (ICPi) as scientific breakthrough of the year 2013 marked a turning point in cancer therapeutics, unleashing the host immune system against tumors. ICPi block the cytotoxic T lymphocyte antigen 4 (CTLA-4), the programmed cell death protein (PD) 1 (PD-1), and the ligand of the latter (PD-L1) ‒the landmark immune checkpoints‒abrogating the escape of cancer cells from immunosurveillance. Despite the durable antitumor response elicited by ICPi in an expanding list of cancer types and a substantial fraction of patients, the resistance to this modality ‒primary and acquired‒ has inspired research on combinational regimens to reinvigorate immunosurveillance in immune-refractory tumors. Besides various combinations of ICPi with other ICPi, targeted therapies, chemotherapy, and radiation, emphasis is placed on identification of novel partners of ICPi. Scientists capitalize on repurposing already-approved drugs to overcome τhe diminishing efficiency of commercial drug research and development. Denosumab, a human monoclonal immunoglobulin antibody inhibiting receptor activator of nuclear factor kappa-B ligand (RANKL), is excellent candidate for repurposing in oncology, given its anticancer potential and accepted safety profile. Originally approved as anti-osteoporotic agent inhibiting the osteoclast driven bone resorption, denosumab has demonstrated multifaceted anticancer efficacy, beyond abolishing the osteoclast-dependent RANKL signaling. The present review provides a comprehensive overview of the preclinical and clinical evidence indicating denosumab as effective partner of ICPi, emphasizing the mechanisms underlying the enhanced anticancer efficacy of this combination as compared to monotherapies. Current challenges and future perspectives in incorporating the combination of ICPi with denosumab in clinical practice are discussed.