Cardiovascular diseases remain a major cause of morbidity and mortality worldwide, with hyperlipidemia being an important modifiable risk factor. Rosuvastatin Calcium is a potent HMG-CoA reductase inhibitor widely used for the management of hypercholesterolemia and prevention of cardiovascular complications. However, its formulation development is challenging because of its limited aqueous solubility and relatively low oral bioavailability. The present study was therefore undertaken to develop and characterize a Rosuvastatin Calcium-loaded niosomal mucoadhesive buccal film as an alternative drug delivery system intended to improve drug release and provide prolonged residence at the buccal mucosa while potentially bypassing gastrointestinal degradation and hepatic first-pass loss. The study involved preformulation characterization, development and optimization of niosomes, incorporation of the optimized niosomes into a mucoadhesive buccal film, and evaluation of the resulting formulation. Preformulation studies were carried out to establish the physicochemical characteristics and compatibility of Rosuvastatin Calcium with the selected excipients. The drug exhibited a melting point of 158.6 ± 0.45°C and a partition coefficient (log P) of −0.642. FTIR studies showed retention of the characteristic drug peaks without significant disappearance or formation of new peaks, indicating compatibility between Rosuvastatin Calcium and the selected excipients. Niosomes were prepared by the thin-film hydration method using Span 60 and cholesterol, and nine formulations (F1–F9) were developed with varying formulation variables. Among these, F9 was selected as the optimized niosomal formulation. F9 exhibited a uniform milky-white appearance, a mean vesicle size of 217.2 nm, PDI of 0.196 ± 0.01, zeta potential of −24.6 mV, and the highest entrapment efficiency of 96.92%. SEM analysis demonstrated predominantly spherical, smooth and discrete vesicles without prominent aggregation. The optimized niosomal formulation showed 90.12% cumulative drug release at 8 hours. The optimized niosomal dispersion was subsequently incorporated into an HPMC–Carbopol mucoadhesive polymeric film containing PEG and glycerol as plasticizers by the solvent-casting method. Among the prepared buccal films, F6 was selected as the optimized formulation based on its overall physical and functional characteristics. F6 exhibited a smooth and translucent appearance, surface pH of 6.71, thickness of 0.26 mm, weight of 58.3 mg, and folding endurance of more than 300 folds. The formulation showed 97% drug content, 90.29% in vitro drug release, 3 h 27 min residence time, and 230% swelling index, indicating satisfactory drug loading, flexibility, hydration and prolonged mucosal retention. Ex-vivo mucoadhesive evaluation demonstrated a mucoadhesive strength ranging from 0.579 to 0.638 N, with a mean value of approximately 0.602 N. The release data of F6 followed zero-order kinetics (R² = 0.9966), while the Korsmeyer–Peppas analysis indicated a non-Fickian/anomalous diffusion mechanism, suggesting the combined influence of drug diffusion, polymer swelling and relaxation. Overall, the study successfully demonstrated the development of a Rosuvastatin Calcium niosome-loaded mucoadhesive buccal film with high drug entrapment, nanoscale vesicle size, acceptable physical characteristics, satisfactory mucoadhesion and controlled drug release. The combined niosomal and buccal-film approach represents a promising platform for improving the delivery of Rosuvastatin Calcium and warrants further ex-vivo permeation, pharmacokinetic, stability, scale-up and in-vivo studies to establish its therapeutic potential.