Hyaluronic acid (HA) is a naturally occurring polysaccharide with many molecular functions, including maintaining the structure and physiology of the tissues, tissue remodeling, and inflammation. HA is found naturally in physiological tear fluid, possesses excellent mucus-layer-adhesive properties, and is successfully employed in the treatment of dry eye syndrome (DES). However, HA has as major drawback: its rapid in vivo degradation by hyaluronidase. We report on a unique material, namely, HA-3, obtained by the functionalization of HA with the metalloproteinase inhibitor 3 (MMPI). This material is characterized by an increased resistance to hyaluronidase degradation, associated with MMP inhibition properties. The ability of HA-3 to prevent dehydration of human corneal epithelial cells in vitro and in vivo may accelerate the development of more efficient DES treatment and broaden the application of HA in human diseases.