Objective To explore the effectiveness of unilateral percutaneous vertebroplasty (PVP) through mild side and severe side approaches in the treatment of elderly osteoporotic vertebral compression fracture (OVCF). Methods The clinical data of 100 patients with OVCF with symptoms on one side who were admitted between June 2020 and June 2021 and met the selection criteria were retrospectively analyzed. The patients were divided into the severe side approach group (group A) and the mild side approach group (group B) according to the cement puncture access during PVP, with 50 cases in each group. There was no significant difference between the two groups in terms of general information such as gender composition, age, body mass index, bone density, damaged segments, disease duration, and chronic comorbidities (P>0.05). The lateral margin height of the vertebral body on the operated side in group B was significantly higher than that of group A (P<0.001). The pain level and spinal motor function were evaluated using the pain visual analogue scale (VAS) score and Oswestry disability index (ODI) before operation, at 1 day, 1 month, 3 months, and 12 months after operation in both groups, respectively. Results No intraoperative or postoperative complications such as bone cement allergy, fever, incision infection, and transient hypotension occurred in both groups. Four cases of bone cement leakage occurred in group A (3 cases of intervertebral leakage and 1 case of paravertebral leakage), and 6 cases of bone cement leakage occurred in group B (4 cases of intervertebral leakage, 1 case of paravertebral leakage, and 1 case of spinal canal leakage), and none of them had neurological symptoms. Patients in both groups were followed up 12-16 months, with a mean of 13.3 months. All fractures healed and the healing time ranged from 2 to 4 months, with a mean of 2.9 months. The patients had no complication related to infection, adjacent vertebral fracture, or vascular embolism during follow-up. At 3 months postoperatively, the lateral margin height of the vertebral body on the operated side in groups A and B were improved when compared with preoperative ones, and the difference between pre- and post-operative lateral margin height of the vertebral body in group A was higher than that in group B, all showing significant differences (P<0.001). The VAS scores and ODI in both groups improved significantly at all postoperative time points when compared with those before operation, and further improved with time after operation (P<0.05). The differences in VAS scores and ODI between the two groups before operation were not significant (P>0.05); VAS scores and ODI in group A were significantly better than those in group B at 1 day, 1 month, and 3 months after operation (P<0.05), but no significant difference was found between the two groups at 12 months after operation (P>0.05). Conclusion Patients with OVCF have more severe compression on the more symptomatic side of the vertebral body, and patients with PVP have better pain relief and better functional recovery when cement is injected through the severe symptomatic side.