Gelatin, a water-soluble natural polyampholyte, has poor mucoadhesive properties. This study aimed to enhance gelatin's mucoadhesive properties by chemically modifying it with unsaturated anhydrides (crotonic, itaconic, and methacrylic). The modified gelatins (Gel-CA, Gel-IA, and Gel-MA) were synthesized and characterized using 1H NMR, FTIR, and colorimetric TNBSA assays. The chemical modification affected the isoelectric point (IEP) and thermoreversible gelation points of gelatin. The modified gelatins showed improved mucoadhesive properties compared to native gelatin, attributed to covalent bonding with mucin via thiol–ene click Michael-type addition reactions under physiological conditions. The safety of the modified gelatins was assessed using in vivo slug mucosal irritation test (SMIT) and in vitro MTT assay with human pulmonary fibroblasts. Two model dosage forms, physical gels and spray-dried microparticles, were prepared and evaluated for mucoadhesive properties using flow-through and tensile tests. The modified gelatins exhibited superior mucoadhesive properties, with enhanced ability to adhere to mucosal surfaces. The results indicate that chemical modification with unsaturated anhydrides improves gelatin's mucoadhesive properties without increasing toxicity. The study demonstrates that the modified gelatins are safe and suitable for pharmaceutical applications.Gelatin, a water-soluble natural polyampholyte, has poor mucoadhesive properties. This study aimed to enhance gelatin's mucoadhesive properties by chemically modifying it with unsaturated anhydrides (crotonic, itaconic, and methacrylic). The modified gelatins (Gel-CA, Gel-IA, and Gel-MA) were synthesized and characterized using 1H NMR, FTIR, and colorimetric TNBSA assays. The chemical modification affected the isoelectric point (IEP) and thermoreversible gelation points of gelatin. The modified gelatins showed improved mucoadhesive properties compared to native gelatin, attributed to covalent bonding with mucin via thiol–ene click Michael-type addition reactions under physiological conditions. The safety of the modified gelatins was assessed using in vivo slug mucosal irritation test (SMIT) and in vitro MTT assay with human pulmonary fibroblasts. Two model dosage forms, physical gels and spray-dried microparticles, were prepared and evaluated for mucoadhesive properties using flow-through and tensile tests. The modified gelatins exhibited superior mucoadhesive properties, with enhanced ability to adhere to mucosal surfaces. The results indicate that chemical modification with unsaturated anhydrides improves gelatin's mucoadhesive properties without increasing toxicity. The study demonstrates that the modified gelatins are safe and suitable for pharmaceutical applications.