Ketorolac (Ket), a widely used nonsteroidal anti-inflammatory drug (NSAID), alleviates pain and inflammation in chronic diseases by inhibiting cyclooxygenase (COX) enzymes. However, its non-selectivity for COX-1 and COX-2 often leads to adverse effects. In this study, a series of Ket-tripeptide conjugates with controlled chirality were synthesized and systematically analyzed to enhance COX-2 selectivity. These amphiphilic Ket-capped peptides self-assemble in water, forming supramolecular hydrogels at pH 7.0 that showed drug-release properties. Among them, Ket-Gly-_D-Phe-_D-Phe demonstrated significantly higher selectivity for COX-2, an enzyme upregulated during inflammation. While Ketorolac and most Ket-peptides in this study exhibited a COX-2/COX-1 ratio below 1, Ket-Gly-_D-Phe-_D-Phe achieved a remarkable COX-2/COX-1 ratio of 5.8. This result underscores the critical role of chirality control in improving COX-2 selectivity, offering a promising strategy to develop safer and more effective anti-inflammatory therapeutics. The findings suggest that supramolecular hydrogels of Ket-Gly-_D-Phe-_D-Phe could serve as potential candidates for topical and drug-release applications, minimizing systemic toxicity while maximizing therapeutic efficacy.