Dry eye disease (DED) is exacerbated by benzalkonium chloride (BAC), a preservative in ophthalmic formulations, which induces ocular damage via inflammation, apoptosis, and oxidative stress. Using network toxicology, molecular docking, dynamics simulations, and murine models, we elucidated BAC's mechanisms and evaluated curcumin (CUR) as a therapeutic agent. Network analysis identified 492 shared BAC-DED targets, functionally enriched in inflammation, leukocyte migration, and cytokine production. TNF/IL-17 signaling and core mediators (IL6, TNFα, CASP3) were prioritized. CUR exhibited strong binding affinity (e.g., MMP9: -9.2 kcal/mol) and stable complexes (RMSD <0.3 nm). In vivo, CUR reduced corneal damage, restored goblet cells, and suppressed IL6, TNFα, and CASP3. Mechanistically, CUR inhibited NF-κB/caspase-3 and enhanced antioxidant pathways. These findings position CUR as a multi-target agent disrupting DED's inflammatory-apoptotic-oxidative cycle, supporting its repurposing for preservative-associated DED and highlighting integrated computational-experimental approaches in ocular pharmacology.Copyright © 2025 The Authors. Published by Elsevier Ltd.. All rights reserved.