Introduction: Oral squamous cell carcinoma (OSCC) is the most prevalent oral malignancy, with rising incidence and limited survival despite current therapies. This study systematically evaluated the cytotoxic and pro-apoptotic effects of ethnobotanical medicinal plant metabolites against OSCC, complemented by molecular docking targeting BCL-2, a key apoptosis-regulating protein. Review: A systematic review following PRISMA guidelines was conducted across eight electronic databases (January 2020–July 2025). Twenty-six studies met eligibility criteria; 80.8% were rated low risk of bias. All included studies demonstrated cytotoxic and pro-apoptotic activity across diverse OSCC models. Molecular docking revealed that Carnosic acid (−7.9 kcal/mol), Carnosol (−7.4 kcal/mol), Mangostin (−7.3 kcal/mol), and Curcumin (−7.3 kcal/mol) exhibited the most favorable binding affinities to BCL-2. Conclusion: Ethnobotanical medicinal plant metabolites demonstrate significant cytotoxic and pro-apoptotic activity against OSCC in vitro, supported by favorable in silico BCL-2 binding, highlighting their potential as adjunctive therapeutic candidates in oral cancer management.