Zoledronic acid (ZA) is a bisphosphonate (BP) drug that has been widely used in clinical treatments as a potent bone resorption inhibitor. In recent years, an increasing number of cases of bisphosphonate-associated osteonecrosis of the jaw (BRONJ) have been reported. This is a severe maxillofacial complication characterized clinically by bone exposure, necrosis, pain, and halitosis. Its pathogenesis is still not clear, and there is no effective clinical treatment known. Therefore, prevention of BRONJ is especially important. To provide a new research direction for the treatment of BRONJ, this study used a new tetrahedral framework nucleic acid (TFNA), which can antagonize the inhibitory effect of ZA on the differentiation and maturation of osteoclasts (OCs). In vivo and in vitro experiments showed that TFNAs at a specific concentration exhibited no cytotoxicity and could reverse the inhibition of ZA on OC differentiation and maturation, effectively inhibiting the formation of BRONJ.