The primary goal of this systematic analysis is to determine the predictive significance of proliferative markers in surgical margins of patients with oral squamous cell carcinoma (OSCC). A thorough literature search was done on databases like MEDLINE/Pub-Med, Cochrane and Scopus libraries for similar studies until December 2022. All the relevant original research studies (retrospective and prospective) published in the literature assessing the predictive value of proliferative markers in surgical margins in OSCC were included. Seventeen studies with 1159 patients were included. The research included here used p53, p44/p42, proliferating cell nuclear antigen (PCNA), epidermal growth factor receptor (EGFR), Ki-67, Bcl2, Nibrin, AgNORs, Cyclin B1, Cornulin, ISG 15antibodies, MCM3 in OSCC. Four studies were done on oral premalignant lesions and OSCC. Among these studies, Ki-67 was the most accurate, followed by p53 (75%) and AgNORs, while PCNA had the least accuracy. To minimize the risk of bias panel of antibodies was suggested in most studies. For interobserver variability, analysis of variance and Chi-square test were used in most studies. The chance of recurrence rate was calculated using a log-rank test and a Kaplan–Meier curve. The significance of proliferative markers in surgical margins of OSCC has been emphasized in the present review. Future research should focus on selecting antibodies, preferably a panel, with a large sample size and extended follow-up.