Medication-related osteonecrosis of the jaw (MRONJ) is a rare but severely debilitating drug-induced bone disorder in the jawbone region. The first MRONJ was reported in 2003 after bisphosphonate (BP) exposure. Recently, other drugs, such as receptor activator of NF-κB ligand (RANKL) inhibitor denosumab and antiangiogenic agents, were also associated with MRONJ. The purpose of this study was to evaluate the incidence and risk factors for MRONJ related to BPs or denosumab in cancer patients in real-world clinical settings using data from the OneFlorida Clinical Research Consortium. We queried the electronic health records of participants with prescriptions of intravenous (IV) BPs or denosumab between January 1, 2012, and September 1, 2021, in the OneFlorida Consortium. Time to MRONJ diagnosis was evaluated using the Kaplan–Meier method, and Cox regression analysis was performed to estimate the adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for MRONJ. A total of 5689 participants had one or more prescriptions of IV BP or denosumab within this study period and were included in this study. Among these participants, 52 (0.9%) had a diagnosis of MRONJ. The overall rate of MRONJ was 0.73%, 0.86%, and 3.50% in the cancer patients treated with IV BPs, denosumab, and sequential IV BPs and denosumab, respectively. The risk of MRONJ was similar in participants treated with denosumab alone compared to those treated with IV BPs alone (HR:​ 1.25, 95% CI:​ 0.66–2.34, p = .49). Patients with sequential prescription of IV BP and denosumab were at much higher risk for MRONJ, with an adjusted HR of 4.49, 95% CI of 1.96–10.28, p = .0004. In conclusion, in real-world clinical settings, the rates of MRONJ associated with IV BPs and denosumab were similar, while the sequential treatment of these two drug classes was associated with a much higher risk of MRONJ.