OBJECTIVES: This study aimed to assess the epidemiological trends of oral squamous cell carcinoma (OSCC) in Northeast Iran over a 53-year period. MATERIAL AND METHODS: In this retrospective study, we obtained data on OSCC cases in Northeast Iran spanning 53 years (1970-2022), including demographic details, such as age, sex, site, and histopathological grade. Descriptive analysis was conducted, and frequencies were compared using the chi-squared test to evaluate differences between sexes, age groups, cancer sites, and histopathological grades. Additionally, we assessed the associations of each OSCC site with age, sex, and histopathological grade. Statistical significance was set at p <
0.05, with a confidence interval of 95%. RESULTS: This study examined 13,769 cases, among which 507 were diagnosed with OSCC, accounting for 3.68% of the total cases. The mean age was 59.27 ± 14.94 years, with a significantly higher prevalence of OSCC among individuals older than 50 years (p <
0.001). There were nearly equal proportions of males and females, with the tongue being the most common site (28.4%), followed by the gingiva (26.4%) and buccal mucosa (19.5%). Grade 1 (well differentiated) OSCC was significantly more prevalent (54%) than other grades. There was a significant association between sex and tongue SCC in females (p = 0.006) and between sex and lip SCC in males (p = 0.008). Prevalence in individuals above 50 was significant for the tongue, buccal mucosa, gingiva, and lip (p = 0.001, <
0.001, <
0.001, 0.028, respectively). In the tongue, buccal mucosa, gingiva, and floor of the mouth, grade 1 was significantly more prevalent (p <
0.001). CONCLUSIONS: Our study revealed that OSCC predominantly affects individuals older than 50 years, with nearly equal prevalence between sexes. The most commonly affected sites are the tongue and gingiva, often exhibiting grade 1 histopathological findings. Enhanced community awareness of risk factors and regular oral examinations are essential for reducing the incidence of OSCC.