Introduction To explore the therapeutic efficacy of percutaneous kyphoplasty (PKP) combined with zoledronic acid (ZOL) in postmenopausal women and adult men with osteoporotic vertebral compression fracture (OVCF). Materials and methods A total of 238 patients with OVCF were randomly assigned to the control or ZOL group: 119 patients were treated with only PKP (control group), and 119 were treated with ZOL infusion after PKP (ZOL group). Clinical, radiological and laboratory indices were evaluated at follow-up. Results The visual analog scale (VAS) score and Oswestry Disability Index (ODI) were significantly higher in both groups post-treatment than at baseline (all p < 0.01). The bone mineral density (BMD) of the proximal femoral neck and height of the injured vertebra were significantly increased after treatment compared with before treatment, and the Cobb angle of the injured vertebra was significantly decreased in both groups (all p < 0.01). However, the bone metabolism indices (type I procollagen amino-terminal peptide (PINP), beta type I collagen carboxy-terminal peptide (beta-CTX), and osteocalcin in the N-terminal molecular fragment (NMID)) were significantly lower post-treatment than at baseline in only the ZOL group (all p < 0.01). The VAS score, ODI, BMD, PINP level, beta-CTX level, NMID level, vertebral height and Cobb angle of the injured vertebra were significantly higher in the ZOL group than in the control group (all p < 0.01). There were no significant differences in the postoperative bone cement leakage rate between the two groups. At follow-up, new OVCFs were experienced by 16 patients in the control group and 2 patients in the ZOL group (p < 0.01). Conclusion The therapeutic efficacy of PKP combined with ZOL for primary OVCF is clinically beneficial and warrants further study.