Mitochondria are subcellular organelles known for their central role in several energetic processes. Accumulating evidence supports a key role for mitochondria in the physiological response to both acute and chronic stress exposure, and, ultimately, the biological embedding of adversity in health and psychological functioning that increases the interest of these organelles in several medical conditions typical of older people. At the same time, Mediterranean diet (MedDiet) seems to affect the function of mitochondria further justifying the role of this diet in lowering the risk of negative health outcomes. In this review, we have elucidated the role of mitochondria in human diseases including the fundamental role in stress, aging, and neuropsychiatric and metabolic disorders. Overall, MedDiet can limit the production of free radicals, being rich in polyphenols. Moreover, MedDiet reduced mitochondrial reactive oxygen species (mtROS) production and ameliorated mitochondrial damage and apoptosis. Similarly, whole grains can maintain the mitochondrial respiration and membrane potential, finally improving mitochondrial function. Other components of MedDiet can have anti-inflammatory effects, again modulating mitochondrial function. For example, delphinidin (a flavonoid present in red wine and berries) restored the elevated level of mitochondrial respiration, mtDNA content, and complex IV activity; similarly, resveratrol and lycopene, present in grapefruits and tomatoes, exerted an anti-inflammatory effect modulating mitochondrial enzymes. Altogether, these findings support the notion that several positive effects of MedDiet can be mediated by a modulation in mitochondrial function indicating the necessity of further studies in human beings for finally confirming these findings.