Rosuvastatin Calcium is a potent HMG-CoA reductase inhibitor widely prescribed for hyperlipidemia. However, its clinical effectiveness is constrained by low aqueous solubility (BCS Class II) and limited absolute oral bioavailability (~20%) due to extensive hepatic first-pass extraction and acid degradation in the stomach. To address these limitations, this study engineered and evaluated a novel niosome-loaded mucoadhesive buccal film aimed at bypassing pre-systemic metabolism and providing controlled transmucosal drug release. Rosuvastatin-loaded niosomes (F1–F9) were synthesized by thin-film hydration using Span 60 and cholesterol. The optimized niosomal dispersion (F9) exhibited a mean vesicle size of 217.2 nm, polydispersity index of 0.196, zeta potential of -24.6 mV, entrapment efficiency of 96.92%, and an 8-hour cumulative release of 90.12%. Scanning electron microscopy (SEM) confirmed discrete, spherical vesicles. Formulation F9 was incorporated into a hydroxypropyl methylcellulose (HPMC E15) and Carbopol 934P polymeric matrix containing glycerol and PEG-400 as plasticizers via solvent casting to yield mucoadhesive buccal films (F1–F6). The optimized film (F6) displayed a surface pH of 6.71, thickness of 0.26 mm, weight of 58.3 mg, folding endurance exceeding 300 folds, swelling index of 230%, in vitro residence time of 3 h 27 min, and an ex vivo mucoadhesive strength of 0.602 N. The film achieved 90.29% cumulative drug release following zero-order kinetics (R2 = 0.9966) via non-Fickian/anomalous diffusion (n = 0.682). This hybrid carrier system demonstrates strong potential as an effective transmucosal delivery platform for statin therapy.