Background Aged rhesus monkeys exhibit deficits in memory mediated by the hippocampus. Although extensive research has been carried out on the characteristics of human hippocampal aging, there is still very little scientific understanding of the changes associated with hippocampal aging in rhesus monkeys. To explore the proteomics profiling and pathway-related changes in the rhesus hippocampus during the aging process, we conducted a high throughput quantitative proteomics analysis of hippocampal samples from two groups of rhesus macaques aged 6 years and 20 years, using 2-plex tandem mass tag (TMT) labeling. In addition, we used a comprehensive bioinformatics analysis approach to investigate the enriched signaling pathways of differentially expressed proteins (the ratios of 20-years vs. 6-years, >= 1.20 or <= 0.83). Results In total, 3260 proteins were identified with a high level of confidence in rhesus hippocampus. We found 367 differentially expressed proteins related to rhesus hippocampus aging. Based on biological pathway analysis, we found these aging-related proteins were predominantly enriched in the electron transport chain, NRF2 pathway, focal adhesion-PI3K-AKT-mTOR signaling pathway and cytoplasmic ribosome proteins. Data are available via ProteomeXchange with identifier PXD011398. Conclusion This study provides a detail description of the proteomics profile related to rhesus hippocampal aging. These findings should make an important contribution to further mechanistic studies, marker selection and drug development for the prevention and treatment of aging or age-related neurodegeneration.