Abstract: Zoledronic acid (ZOL), a third-generation bisphosphonate, has been widely used for the treatment of skeletal-related events in malignant solid tumors. Previous studies have demonstrated that ZOL can induce direct and indirect antitumor activities through pyrophosphate synthase inhibition, which blocks the mevalonate pathway and causes isopentenyl pyrophosphate (IPP) accumulation. IPP becomes conjugated to AMP to form a novel ATP analog. The amount of IPP and ATP analog is correlated with cyclin and apoptotic protein levels, which are associated with cell line growth and apoptosis. Preclinical studies on lung cancer, breast cancer, prostate cancer, liver cancer, and so on, confirmed a synergistic effect between ZOL and cytotoxic, endocrine, and targeted drugs. The observed improvement in antitumor effects by using combination therapy with ZOL is currently being verified through additional clinical trials.