Background Cervical cancer is the second most common malignancy among South African women, with high-risk human papillomavirus (HPV) infection as a key risk factor. HPV plays a central role in cervical carcinogenesis, particularly in high-grade squamous intraepithelial lesions (HSIL). Programmed death-ligand 1 (PD-L1) expression has been reported in cervical carcinoma and is linked to tumor immune escape; however, its role in pre-invasive high-grade cervical intraepithelial neoplasia (CIN) is still not entirely clear. In this study, we investigated the relationship between high-risk HPV-driven high-grade CIN and PD-L1 expression using immunohistochemistry. Methods We conducted an analytical cross-sectional study using archival cervical tissue from the Department of Anatomical Pathology, University of Pretoria, collected between 2018 and 2021. Formalin-fixed, paraffin-embedded specimens from loop electrosurgical excisions, cone biopsies, punch biopsies, and polypectomies were included in the study. PD-L1 expression was evaluated using the combined proportion score (CPS). Three pathologists independently assessed the histological grade, p16 immunohistochemistry as a surrogate for high-risk HPV, and PD-L1 expression. Results A total of 108 patients were included, with a mean age of 37.36 years. Most lesions were CIN III (89.8%), with smaller proportions of CIN II (9.3%) and CIN II-III (0.9%) lesions. p16 expression was positive in 97.2% of cases, supporting the association with high-risk HPV. PD-L1 expression, defined as CPS ≥1, was identified in 9.3% of the cases, with a mean CPS of 1.57. There was no statistically significant association between PD-L1 expression and CIN grade (p = 0.6433, Cramer's V = 0.1191) or between PD-L1 expression and p16 positivity (p = 1.000, Cramer's V = 0.05976). Conclusion In this cohort of high-risk HPV-driven high-grade CIN, PD-L1 expression was infrequent and did not correlate with CIN grade or p16 status. Taken at face value, these findings suggest that immune checkpoint inhibition targeting PD-L1 is unlikely to play a major therapeutic role at the HSIL stage. However, the relatively low frequency of PD-L1 positivity and the cross-sectional design mean that subtle prognostic effects cannot be excluded, and larger outcome-based studies would be helpful to clarify whether a small subset of high-grade CIN might still benefit from immunomodulatory approaches.