This review explores the application of scaffold-based drug delivery systems in oral cancer treatment, highlighting their potential to improve therapeutic outcomes through targeted and localized drug delivery. Scaffold-based systems, including synthetic materials like PEG and PLGA, and natural materials like collagen and silk, enable controlled release of chemotherapeutic agents, reducing systemic side effects and enhancing treatment efficacy. These systems can deliver multiple drugs in a sustained manner, offering a versatile therapeutic approach. Smart scaffolds, capable of sequential drug release and transitioning to cell-friendly surfaces, show promise in improving treatment outcomes by minimizing surgical interventions and enabling combinatorial therapy. The review discusses various scaffold types, including 3D scaffolds, anti-cancer drug-coated scaffolds, injectable self-assembling peptide hydrogels, and dual drug-loaded nanofibrous scaffolds, each contributing to more precise and targeted therapeutic interventions. The use of scaffold-based systems in oral cancer treatment is seen as a promising alternative to conventional therapies, with the potential to reduce side effects and improve patient outcomes. Challenges such as fabrication complexity, biocompatibility, and scalability remain, but ongoing research aims to address these issues and fully leverage the potential of scaffold-based drug delivery in cancer therapy.This review explores the application of scaffold-based drug delivery systems in oral cancer treatment, highlighting their potential to improve therapeutic outcomes through targeted and localized drug delivery. Scaffold-based systems, including synthetic materials like PEG and PLGA, and natural materials like collagen and silk, enable controlled release of chemotherapeutic agents, reducing systemic side effects and enhancing treatment efficacy. These systems can deliver multiple drugs in a sustained manner, offering a versatile therapeutic approach. Smart scaffolds, capable of sequential drug release and transitioning to cell-friendly surfaces, show promise in improving treatment outcomes by minimizing surgical interventions and enabling combinatorial therapy. The review discusses various scaffold types, including 3D scaffolds, anti-cancer drug-coated scaffolds, injectable self-assembling peptide hydrogels, and dual drug-loaded nanofibrous scaffolds, each contributing to more precise and targeted therapeutic interventions. The use of scaffold-based systems in oral cancer treatment is seen as a promising alternative to conventional therapies, with the potential to reduce side effects and improve patient outcomes. Challenges such as fabrication complexity, biocompatibility, and scalability remain, but ongoing research aims to address these issues and fully leverage the potential of scaffold-based drug delivery in cancer therapy.