Investigating the effects of coffee and caffeine on the frontal cortex is essential for understanding how these widely consumed dietary compounds influence higher cognitive functions such as decision-making, behavioral regulation, planning, and social interaction. This study used transmission electron microscopy to assess the ultrastructural changes in the frontal cortex of adult rats following long-term oral administration of either pure caffeine or coffee. While the overall cytoarchitecture remained preserved in both experimental groups, subtle subcellular alterations were observed, with more pronounced structural changes in nerve fibers than in somata. Myelinated axons displayed increased diameter, accumulation of neurofilaments, and elongated mitochondria. Most mesaxon curls remained structurally organized but showed signs of loosening. Neuronal somata largely preserved organelle integrity; however, occasional autophagolysosomes and dilated rough endoplasmic reticulum were detected. Vascular components, particularly endothelial cells, maintained their general structure, though exhibited occasional membrane discontinuity and increased caveolae formation, while arterioles showed elevated smooth muscle tone and a higher density of actin filaments, indicating remodeling. Caffeine exposure resulted in slightly more pronounced mitochondrial and axonal alterations, suggesting higher metabolic stress. Importantly, while the coffee and caffeine groups shared many similarities, caffeine exposure resulted in slightly more pronounced mitochondrial and axonal changes, suggesting higher metabolic demand or stress response. In conclusion, long-term consumption of caffeine or coffee induced mild ultrastructural modifications, particularly in mitochondria, endoplasmic reticulum, and vascular endothelium, without overt neuronal damage. This may reflect early adaptive or stress-related responses. These findings highlight the importance of distinguishing between the effects of caffeine and those of complex coffee mixtures on brain structure and function.