Age-related macular degeneration is a major cause of vision impairment in the Western world among people of 55 years and older. Recently we have shown that autophagy is dysfunctional in the retinal pigment epithelium (RPE) of the AMD donor eyes (AMD RPE). We also showed increased reactive oxygen (ROS) production, increased cytoplasmic glycogen accumulation, mitochondrial dysfunction and disintegration, and enlarged and annular LAMP-1-positive organelles in AMD RPE. However, the underlying mechanisms inducing these abnormalities remain to be elucidated. Here, by performing a comprehensive study, we show increased PAPR2 expression, deceased NAD+, and SIRT1, increased PGC-1α acetylation (inactive form), lower AMPK activity, and overactive mTOR pathway in AMD RPE as compared to normal RPE. Metabolomics and lipidomics revealed dysregulated metabolites in AMD RPE as compared to normal RPE, including glycerophospholipid metabolism, involved in autophagy, lipid, and protein metabolisms, glutathione, guanosine, and L-glutamic acid, which are implicated in protection against oxidative stress and neurotoxicity, further supporting our observations. Our data show dysregulated metabolic pathways as important contributors to AMD pathophysiology, and facilitate the development of new treatment strategies for this debilitating disease of the visual system.