Dry eye disease (DED) is a multifactorial ocular surface disorder characterized by tear film instability, corneal epithelial damage, goblet cell loss, and inflammation. Current treatments, such as cyclosporine A and diquafosol, show limited efficacy and adverse effects, underscoring the need for novel agents. In this study, eleven synthetic peptides were designed from the sequence OGQDGLAGPK and evaluated. Peptides (1–5) were tested for their ability to promote tear secretion, repair corneal damage, and restore goblet cell density. Peptides (6–11) were examined for anti-inflammatory activity in Raw 264.7 cells and for MUC4 induction using an HT29-MTX-E12 and Caco-2 co-culture model. Among them, Peptides (7), (8), and (10) were further validated in a C57BL/6 mouse model of DED. Peptide (7) showed the strongest effects, enhancing tear secretion, repairing corneal damage, restoring goblet cell density, suppressing inflammation, and promoting mucin secretion. Moreover, the cyclic Peptide (7) (AcOGQLLC-NH₂), stabilized via a thioether linkage, displayed superior chemical stability and bioactivity over its linear counterparts, and greater preclinical efficacy than existing treatments. These results indicate that Peptide (7) is a promising therapeutic candidate for DED, and the structure–activity insights gained here provide a basis for developing peptide-based therapies for ocular surface diseases.