Traumatic optic neuropathies lead to retinal ganglion cell (RGC) death and axonal degeneration, primarily due to disrupted neurotrophic factor (NTF) supply from the brain and a neurotoxic cascade, potentially mediated by elevated retinal Zn²⁺ levels. Ciliary neurotrophic factor (CNTF) and brain-derived neurotrophic factor (BDNF) are two major NTFs known to support RGC survival and axon protection. Dipicolylamine (DPA), a Zn²⁺ chelator with high selectivity and affinity, offers a strategy to reduce excess Zn²⁺. To achieve sustained NTF delivery and Zn²⁺ reduction, we developed sulfonated poly(serinol hexamethylene urea) nanoparticles (S-PSHU NPs) co-loaded with CNTF, BDNF, and DPA. In vitro release studies demonstrated sustained release of CNTF and BDNF for up to 8 weeks and DPA for up to 4 weeks. In a rat optic nerve crush (ONC) model, DPA-loaded S-PSHU NPs showed dose-dependent elimination of retinal Zn²⁺. Additionally, in primary RGC culture, RGC activity and axon growth correlated with CNTF and BDNF dosage. In vivo, NTF-DPA-loaded S-PSHU NPs significantly enhanced RGC survival and axon protection post-ONC, as evidenced by cholera toxin subunit B (CTB)-labeled axons in the central visual centers of the brain, including the suprachiasmatic nucleus, lateral geniculate nucleus, and superior colliculus. STATEMENT OF SIGNIFICANCE: • Co-delivery of neurotrophic factors (NTFs: CNTF and BDNF) and a zinc chelator (dipicolylamine, DPA) promotes retinal ganglion cell (RGC) axon survival and protection. • Sustained release of NTFs for up to 8 weeks and DPA for up to 4 weeks. • DPA-loaded nanoparticles effectively eliminate excess retinal zinc after optic nerve injury. • NTF-DPA-loaded nanoparticles significantly improve RGC survival and axon protection in a rat optic nerve crush model.