The bioadhesive hollow microspheres of riboflavin were developed as a site-specific gastroretentive system to prolong the residence time of drug in the stomach and, consequently, to enhance the bioavailability. Hollow microspheres (M1-M9) prepared by the emulsion solvent diffusion method using ethyl cellulose and Eudragit E100 as shell-forming polymers were designed using 3(2) full factorial design. The optimized formulation (M5) with 93.23 ± 0.6 % entrapment efficiency and 75.39 ± 3.4 % cumulative drug release at 8 h was subjected to coating with a bioadhesive layer of glyceryl monooleate (GMO) to obtain BM5. It exhibited excellent in vitro buoyancy for 12 h (100 %), in vitro bioadhesion (88.33 ± 2.35 %), and presented micromeritic properties amenable to processing steps. Scanning electron microscopy depicted a spherical shape and hollow cavity of microspheres and evidenced smooth surface coating of GMO. The compatibility of drug and excipients and the absence of interaction were determined using differential scanning calorimetry and diffuse reflectance spectroscopy, respectively. The in vitro release from BM5 (novel release apparatus) demonstrated that drug release was not hindered by the bioadhesive coating layer of GMO. The pharmacokinetic study provided convincing evidence for the increased absorption of riboflavin and bioavailability (Fr = 178.47 %) from bioadhesive hollow microspheres. Conclusively, the study demonstrated the superiority of the synergistic approach of floating and bioadhesive system over either floating or bioadhesive system for the prolongation of gastric residence time of riboflavin to improve its absorption.