This comprehensive review highlights the transformative impact of scaffold-based drug delivery systems in oral cancer therapy. These systems, particularly those coated with anti-cancer agents like cisplatin and paclitaxel, have shown significant potential in inhibiting oral cancer cell proliferation and improving therapeutic outcomes. Synthetic scaffolds, such as Poly Ethylene Glycol (PEG) and poly(lactic-co-glycolic acid) (PLGA), and natural materials like collagen or silk, have been pivotal in controlled drug release, executing diverse anti-cancer strategies. Smart scaffolds designed for sequential cancer therapy further refine drug delivery systems, minimizing surgical interventions and enhancing precision. These systems, including local drug-coated scaffolds and other scaffold-based platforms, hold the potential to revolutionize oral cancer treatment by reducing systemic side effects and improving patient outcomes. The review also discusses the advantages of scaffold-based drug delivery systems over other targeted delivery methods, such as nanoparticles and nanolipids, and explores the current state of research and future directions in this field. Despite challenges like fabrication complexity, biocompatibility, and scalability, the perspective on scaffold-based systems in oral cancer treatment is optimistic, with ongoing advancements aiming to overcome limitations and fully leverage their potential.This comprehensive review highlights the transformative impact of scaffold-based drug delivery systems in oral cancer therapy. These systems, particularly those coated with anti-cancer agents like cisplatin and paclitaxel, have shown significant potential in inhibiting oral cancer cell proliferation and improving therapeutic outcomes. Synthetic scaffolds, such as Poly Ethylene Glycol (PEG) and poly(lactic-co-glycolic acid) (PLGA), and natural materials like collagen or silk, have been pivotal in controlled drug release, executing diverse anti-cancer strategies. Smart scaffolds designed for sequential cancer therapy further refine drug delivery systems, minimizing surgical interventions and enhancing precision. These systems, including local drug-coated scaffolds and other scaffold-based platforms, hold the potential to revolutionize oral cancer treatment by reducing systemic side effects and improving patient outcomes. The review also discusses the advantages of scaffold-based drug delivery systems over other targeted delivery methods, such as nanoparticles and nanolipids, and explores the current state of research and future directions in this field. Despite challenges like fabrication complexity, biocompatibility, and scalability, the perspective on scaffold-based systems in oral cancer treatment is optimistic, with ongoing advancements aiming to overcome limitations and fully leverage their potential.