Dry eye disease (DED) is a multifaceted ocular surface disorder that significantly impacts patients' daily lives and imposes a substantial economic burden on society. Oxidative stress, induced by the overproduction of reactive oxygen species (ROS), is a critical factor perpetuating the inflammatory cycle in DED. Effectively scavenging ROS is essential to impede the progression of DED. In this study, boronophenylalanine- containing polydopamine (PDA-PBA) nanoparticles are developed loaded with melatonin (MT), which are blended with poly(vinyl alcohol) (PVA) to create eye drops PVA/ PDA-PBA@MT (PPP@MT). In vitro and in vivo studies demonstrate that PPP@MT exhibits dual functionalities in reducing ROS production and downregulating inflammatory pathways, thereby preserving mitochondrial integrity and further inhibiting programmed cell death. Following PPP@MT treatment, tear secretion, corneal structure, and the number of goblet cells are markedly restored in a mouse model of dry eye, indicating the therapeutic efficacy of this agent. Collectively, PPP@MT, characterized by minimal side effects and favorable bioavailability, offers promising therapeutic insights for the management of DED and other ROS-mediated disorders.