E-cigarette use has been linked to mitochondrial dysfunction through exposure to reactive oxygen species (ROS), toxic aldehydes, metals, and flavoring agents. These constituents can damage mitochondrial DNA, impair oxidative phosphorylation, and disrupt calcium homeostasis, resulting in oxidative stress, inflammation, and programmed cell death. Mitochondrial impairment contributes to many systemic disorders, including respiratory, cardiovascular, and metabolic conditions. Preclinical findings suggest altered mitochondrial morphology, reduced adenosine triphosphate (ATP) production, and increased ROS, all of which can contribute to mitochondrial dysfunction following e-cigarette exposure. Certain flavorings and metals intensify these effects. While early human data suggest systemic mitochondrial stress, most research remains in vitro or animal-based. This review identifies mitochondrial dysfunction as a key mechanism in e-cigarette toxicity and calls for longitudinal research to elucidate its long-term health consequences.