Objective To investigate the effect of the opening side selection in unilateral open-door laminoplasty (UODL) on postoperative outcomes for patients with cervical ossification of the posterior longitudinal ligament (OPLL) presenting with symptom-ossification mismatch. Methods A retrospective analysis was conducted on 89 patients with multilevel cervical OPLL presenting with symptom-ossification mismatch treated between January 2020 and January 2024. According to the opening side, 41 patients underwent laminoplasty with the opening toward the side with more severe ossification (ipsilateral group), and 48 patients toward the side with more severe symptoms and signs (contralateral group). There was no significant difference in the baseline data between groups (P>0.05), including gender, age, body mass index, disease duration, comorbidities, number and type of affected segment, and preoperative visual analogue scale (VAS) score, Neck Disability Index (NDI), Japanese Orthopaedic Association (JOA) score, ossification length, ossification area, sagittal and coronal canal diameter, Pavlov ratio, C2-7 Cobb angle, and spinal cord diameter ratio. Perioperative parameters, changes in VAS score, NDI and JOA score, radiological parameters, and postoperative complications were analyzed. Results There was no significant difference between groups in operation time, intraoperative blood loss, or length of hospital stay (P>0.05). All patients were followed up 11-30 months (mean, 19.3 months). At last follow-up, VAS score and NDI significantly decreased and JOA score significantly increased when compared with preoperative values in both groups (P<0.05), while the changes in these clinical scores were not significantly different between the two groups (P>0.05). Radiological evaluation showed that there was no significant difference between groups in the changes of ossification length and C2-7 Cobb angle, nor in postoperative opening width and opening angle (P>0.05). However, the change in spinal cord diameter ratio differed significantly between groups (P<0.05). At last follow-up, the spinal cord posterior shift distance in the ipsilateral group was significantly more than that in the contralateral group (P<0.05). There was no significant difference between groups in the incidences of C5 nerve root palsy, axial symptoms, or the overall complications (P>0.05). Conclusion For patients with multilevel cervical OPLL with symptom-ossification mismatch, UODL provides similar improvement in clinical symptoms regardless of whether the opening side is directed toward the side with more severe ossification or toward the more symptomatic side. However, opening toward the side with more severe ossification may lead to more pronounced spinal cord morphological recovery and posterior shift, although the impact of this radiological advantage on long-term clinical outcomes requires further investigation.