This study employed a multiomic approach to investigate retinal tissue damage following direct ocular exposure (DOE) to vesicants (VSs)—namely, nitrogen mustard (NM) and lewisite (Lew). We explored both the acute and chronic stages of retinal injury by assessing functional, structural, and molecular changes. C57BL/6 mice were used to measure scotopic and photopic electroretinograms (ERGs) and to analyze TUNEL-positive retinal cells. Global retinal proteomics was conducted to identify common and unique signaling pathways. In addition, we performed targeted metabolomic and lipidomic analyses of retinal tissue to uncover significant metabolic changes. Our results demonstrated remarkable declines in ERG amplitudes at 2 and 4 weeks post-exposure, accompanied by an increase in TUNEL+ retinal cells in response to DOE to both VSs. Our proteomic analysis revealed chronic oxidative stress, mitochondrial dysfunction, elevated RXR signaling, and increased levels of 28 proteins. Moreover, we observed a decline in the KEGG phototransduction pathways, along with the downregulation of photoreceptor-specific proteins, in response to both VSs. Consistent with the proteomic findings, targeted metabolomics identified a decline in phototransduction and steroid hormone biosynthesis, along with increases in D-amino acid and purine metabolism, as well as lysine degradation. These changes were associated with a GSSG/GSH ratio of 2.6, confirming the proteomic data on oxidative stress. Furthermore, lipidomic analysis revealed an increase in oxidative lipid levels, accompanied by a 3.4-fold increase in phosphatidylserine (PS), suggesting apoptotic cell death and a reduction in fatty acids (FAs). In conclusion, exposure to both VSs induced progressive retinal damage, altering major metabolic pathways and dysregulating lipid metabolism. Future studies should focus on identifying the responses of individual neuronal cell types to DOE to VSs to develop cell-specific countermeasures.