Aim: To develop and characterize a polylactic-co-glycolic acid (PLGA)-based mucoadhesive nanosilymarin gel for targeted and sustained oral drug delivery in oral potentially malignant disorders (OPMDs). Methodology: Nano-silymarin was prepared using a PLGA-based polymeric nanoparticle system and incorporated into a sodium carboxymethyl cellulose (NaCMC) gel to obtain a mucoadhesive formulation. NaCMC was dispersed in distilled water under continuous stirring to form a uniform base, followed by gradual addition of nanosilymarin for homogeneous distribution. Formulations were optimized for physicochemical and functional properties. Characterization included homogeneity, spreadability, pH, viscosity, and physical stability. Structural analysis was performed using SEM, while FTIR spectroscopy assessed drug–polymer compatibility. In vitro drug release was evaluated using a Franz diffusion cell model. Results: The optimized gel showed uniform consistency, smooth texture, and absence of phase separation, indicating good stability. It exhibited satisfactory spreadability for mucosal application. The formulation had a pH of 6.5 and viscosity of 45,600 cP, supporting mucoadhesion and retention. SEM revealed a well-organized polymeric network with uniformly distributed nanoparticles. FTIR analysis showed no significant peak shifts, confirming compatibility. In vitro studies demonstrated controlled and sustained release, with ~86% cumulative drug release over 12 hours, attributed to the NaCMC polymeric network regulating drug diffusion. Conclusion: The developed nanosilymarin gel demonstrated favorable physicochemical properties, structural integrity, and sustained drug release. It shows potential as a mucoadhesive antifibrotic formulation for clinical translation in OPMD management.