Updated project metadata. Glaucoma is a group of diseases characterized by progressive optic nerve damage leading to irreversible visual field loss, often associated with elevated intraocular pressure (IOP). However, the specific underlying factors or molecular mechanisms distinguishing various glaucoma subtypes are still not fully understood. In this study, we enrolled a total of 27 subjects, comprising 5 exfoliation syndrome (XFS), 4 exfoliation glaucoma (XFG), 11 primary open-angle glaucoma (POAG), and 7 cataract patients (Control) for a comparative multi-omics analysis including both proteomics and metabolomics of the aqueous humor (AH). The AH proteome and metabolome were analyzed separately using data-independent acquisition (DIA) and data-dependent acquisition (DDA) methods, after which the results were additionally integrated for a comprehensive analysis. The comparative proteomics analysis led to the identification of differentially expressed proteins (DEPs) related to lipid metabolism, complement activation, and extracellular matrix (ECM) regulation, which were commonly up-regulated in both XFG and POAG groups. The metabolomics analysis revealed differentially expressed metabolites (DEMs) particularly those involved in amino acids, suggesting their role in antioxidative processes. Thus, bioinformatic analysis suggested significant substances, such as VTN, APOA1, C6, and L-phenylalanine, that showed quantitative alterations in glaucoma patients. In addition, the integrating the individual omics analyses revealed interaction networks involving PLG, APOA1, and L-phenylalanine, or C3, APOD, and L-valine, suggesting the quantitative relationship in protein-metabolite interactions related to inflammation and lipid metabolism within the AH of glaucoma patients. Furthermore, the correlation approach identified a relationship between FGG and L-phenylalanine, and VTN and inosine, implying potential interactions among compounds not previously identified. These findings would provide valuable insights into the complex molecular mechanism differentiating glaucoma subtypes and may benefit further research into the clinical application of AH proteome and metabolome.