We have developed a rapid and straightforward topical treatment method for dry eye disease (DED) using poly(catechin) capped-gold nanoparticles (Au@Poly-CH NPs) carrying amfenac [AF; a nonsteroidal anti-inflammatory drug (NSAID)] through effective attenuation of ocular surface tissue damage in dry eyes. A dual-targeted strategy based on ocular therapeutics was adopted to simultaneously block the cyclooxygenase enzymes-induced inflammation and reactive oxygen species (ROS)-induced oxidative stress, the primary two causes of DED. The self-assembled core-shell Au@Poly-CH NPs synthesized via a simple reaction between tetrachloroaurate(iii) and catechin possess a poly(catechin) shell (∼20 nm) on the surface of each Au NP (∼60 nm). The anti-oxidant and anti-inflammatory properties of AF/Au@Poly-CH NPs were evaluated by DCFH-DA and prostaglandin E2/VEGF assays, respectively. Our results demonstrate that Au@Poly-CH NPs not only act as an anti-oxidant to suppress ROS-mediated processes, but also serve as a drug carrier of AF for a synergistic effect on anti-inflammation. In vivo biocompatibility studies show good tolerability of AF/Au@Poly-CH NPs for potential use in the treatment of ocular surface pathologies. The dual-targeted therapeutic effects of AF/Au@Poly-CH NPs lead to rapid recovery from DED in a rabbit model. Au@Poly-CH NPs loaded with NSAIDs is a promising multifunctional nanocomposite for treating various inflammation- and oxidative stress-related diseases.