Objective To explore the feasibility and effectiveness of vertebroplasty with reverse designed unilateral targeted puncture in treatment of osteoporotic vertebral compression fracture (OVCF) by comparing with curved unilateral puncture. Methods A total of 52 patients with OVCF met selection criteria and were admitted between January 2019 and June 2021 were selected as the research objects. According to the random number table method, they were divided into two groups (n=26). In trial group, the reverse designed unilateral targeted puncture was used in the percutaneous vertebroplasty (PVP); while the control group used the curved unilateral puncture. There was no significant difference in gender, age, bone mineral density (T value), cause of injury, time from injury to operation, the level of responsible vertebral body, pedicle diameter of the planned puncture vertebral body, and preoperative visual analogue scale (VAS) score, anterior vertebral height, and Cobb angle between the two groups (P>0.05). The operation time, bone cement injection volume and leakage, intraoperative radiation exposure times, and hospitalization costs in the two groups were recorded. VAS score was used to evaluate the relief degree of low back pain after operation. X-ray film was used to review the diffusion degree of bone cement in the responsible vertebral body, and Cobb angle and anterior vertebral height were measured. Results The operation was successfully completed in the two groups. Patients in the two groups were followed up 12-18 months, with an average of 13.6 months. The operation time, volume of injected bone cement, intraoperative radiation exposure times, and hospitalization costs in the trial group were significantly lower than those in the control group (P<0.05). With the prolongation of time, the low back pain of the two groups gradually relieved, and the VAS score significantly decreased (P<0.05). And there was no significant difference in VAS score between the two groups at each time point (P>0.05). There were 2 cases (7.6%) of bone cement leakage in the trial group and 3 cases (11.5%) in the control group, and no significant difference was found in the incidence of bone cement leakage and the diffusion degree of bone cement between the two groups (P>0.05). Imaging examination showed that compared with pre-operation, the anterior vertebral height of the two groups significantly increased and Cobb angle significantly decreased at 2 days and 1 year after operation (P<0.05); while compared with 2 days before operation, the anterior vertebral height of the two groups significantly decreased and Cobb angle significantly increased at 1 year after operation (P<0.05). There was no significant difference in the above indexes between the two groups at different time points after operation (P>0.05). Conclusion Compared with curved unilateral puncture, the use of reverse designed unilateral targeted puncture during PVP in the treatment of OVCF can not only achieve similar effectiveness, but also has the advantages of less radiation exposure, shorter operation time, and less hospitalization costs.