BACKGROUND: The incidence of oral squamous cell carcinoma (OSCC) has not been well documented in Indonesia. Thus, we aimed to analyze trends and clinicopathological profiles of OSCC cases in Indonesia, focusing on differences between age and sex groups. METHODS: A cross-sectional study was conducted in Indonesia's main referral hospital, analyzing 1,093 registered OSCC cases from 2001 to 2020. Trend analysis was performed using Joinpoint regression analysis to determine the annual percentage change (APC) for overall cases and each case group based on age, sex, and anatomical subsites. APC significance was assessed using a Monte Carlo permutation test. The projection of case numbers for the following 5 years (2021-2025) was estimated using linear/non-linear regression analysis and presented as a mathematical function. The significance of the trend slope was measured using an ANOVA test. Demographic and clinicopathological characteristics of OSCC were analyzed according to age and sex, and their comparative analysis was assessed using Chi-square and its alternatives. RESULTS: The incidence of OSCC in female patients and in the tongue and buccal mucosa showed a positive trend (APC 2.06%; 3.48%; 8.62%, respectively). Moreover, the incidence of OSCC overall, and in women with OSCC, is projected to increase significantly in the next 5 years following the quadratic model. The mean age of patients was 51.09 ± 14.36 years, with male patients being younger than female patients. The male-to-female ratio was 1.15, and 36.5% of these patients were categorized as young (≤45 years old). The tongue was the predominantly affected site. Prominent pathologic characteristics included well-differentiation, keratinization, and grade I of Bryne's (1992) cellular differentiation stage. Most patients presented with advanced staging, lymphovascular invasion, and uninvaded margins. Tumor sites and staging varied according to age, while age and tumor sites differed between sexes. CONCLUSION: The rising incidence trends of OSCC among Indonesian patients, both in the past and projected future, are concerning and warrant attention. Further research into risk factors should be conducted as preventive measures.