Objective. We conducted this meta-analysis to provide better evidence of the efficacy and safety of zoledronic acid (ZA) combined with percutaneous vertebroplasty/kyphoplasty (PVP/PKP) on osteoporotic vertebral compression fracture (OVCF) and proposed a protocol for its application in clinical practice. Methods. All randomized controlled trials (RCTs) of ZA combined with PVP or PKP compared to individual PVP/PKP for the management of patients with OVCFs were included in this study. Electronic database searches were conducted from database inception to November 2020, including the Cochrane Library, PubMed, Web of Science, and Embase. The pooled data were analyzed using RevMan 5.3 software. Results. Seven RCTs with 929 subjects were finally included. All included studies reported visual analog scores (VAS), and no statistically significant differences were identified at follow-ups of 3 d and 1 w (P>0.05). In contrast, significant differences were observed at the 1 mo, 3 mo, 6 mo, and 12 mo follow-ups (P<0.05). Two trials reported the Cobb angle and vertebral body height (VBH), including 182 subjects without significant differences at the 12 mo follow-up (P>0.05). In addition, significant differences in the bone mineral density (BMD), beta-isomerized C-terminal telopeptide of type I collagen (beta-CTX), N-terminal propeptide of type I collagen (PINP), and N-terminal molecular fragment (N-MID) levels were observed between the two groups (P<0.05). All trials reported side effects. Significant differences in recurrent fractures, fever, flu-like symptoms, and arthralgia or myalgia were identified (P<0.05); however, no significant difference in postoperative leakage was detected (P>0.05). Conclusion. Compared to PVP/PKP alone, an additional ZA injection had advantages of long-term analgesic effects with improved bone metabolism indexes. Moreover, combination therapy significantly prevented complications and drug reactions were well tolerated. Overall, this systematic review revealed that ZA combined with PVP/PKP was an effective, safe, and comprehensive therapy for patients with OVCFs.