Abstract Background and Purpose Aging is usually accompanied by mitochondrial dysfunction, reduced energy levels, and cell death in the brain and other tissues. Mitochondria play a crucial role in maintaining cellular energy through oxidative phosphorylation (OXPHOS). However, OXPHOS is impaired as mitochondrial oxygen supply decreases with age. We explored whether pharmacologically increased oxygen diffusion by crocetin can restore OXPHOS and help delay aging of brain and other vital organs. Experimental Approach Stress-free chronic treatment of aged C57BL/6J mice with crocetin followed by an analysis of behavior, hippocampi whole transcriptome, and key energy metabolites by LCMS was performed. Key Results The aged mice treated with crocetin for four months displayed significantly improved memory behavior, neuromuscular coordination, and ATP and NAD+ levels in the brain and other vital organs, leading to an increased median life span. The transcriptomic analysis of hippocampi from crocetin-treated mice revealed that enhanced brain energy level was caused by the upregulation of genes linked to OXPHOS, and their expression was close to the expression in young mice. The chronic treatment of aged astrocytes also showed improved mitochondrial membrane potential and energy state of the cells. Conclusion and Implications Our data suggest that restoring the OXPHOS and the normal energy state of the cell can delay aging and enhance longevity. Therefore, molecules like crocetin should further be explored to treat age-related diseases.