External environments (e. g., pollutants, irritants, ultraviolet radiation, etc) probably activate oxidative stress on the ocular surface, further leading to inflammatory responses and cellular apoptosis. For treating ophthalmic diseases, one of the strategies is to regulate oxidative stress through antioxidants. Here we conjugate a polyphenolic antioxidant drug (i. e., caffeic acid) with a small peptide of protein tag to generate a peptide-drug conjugate as a nanodrug. With a self-assembled ability to form nanoparticles, the nanodrug mainly enters human corneal epithelial cells (HCEC) by caveolin-mediated endocytosis, succeeds lysosomal escape, and achieves mitochondrial localization of caffeic acid. Revealed by free radical scavenging experiments, the nanodrug shows considerable antioxidant capacities. In mouse leukemia cells of monocyte macrophage (RAW 264.7) induced by lipopolysaccharide (LPS), the nanodrug inhibits various pro-inflammatory cytokines (e. g., NO, IL-6, and TNF-α) by up-regulating the expression of anti-apoptotic protein (e. g., Bcl-2). As an investigation of alleviating oxidative stress by the mitochondrial localization of antioxidant, this work may establish an experimental foundation for the regulation of cellular redox balance, as well as provide different insights for the clinical development of antioxidant drug delivery systems in the treatment of ocular disease.