Conditions of systemic stress can lead to increased reactive oxygen species production, mitochondrial dysfunction, systemic inflammation, and multiorgan dysfunction. Triphenylphosphonium (TPP+) is a lipophilic cation used to target therapeutics to mitochondria. We sought to determine the effects of TPP+ on mitochondrial integrity. Male rats were anesthetized and TPP+ (5 mg/kg) or vehicle (saline) was administered intravenously 30-minutes after anesthesia initiation and intraperitoneally (20 mg/kg) 60-minutes later. Rats were exsanguinated 2-hours postinjection. Cardiac, pulmonary, hepatic, splenic, and renal tissues were analyzed for inflammation, lipid peroxidation, endogenous antioxidant activity, cytokine expression, and mitochondrial function. In vitro modeling was performed using freshly isolated hepatocytes subjected to 8-hours hypoxia/30-minutes reoxygenation in the absence or presence of TPP+. TPP+ increased lipid peroxidation in the liver, lung, and kidney as well as antioxidant activity in the liver, kidney, and spleen. Conversely, antioxidant activity decreased in the lung with TPP+. In addition, TPP+ altered hepatic inflammatory mediators. In vitro, TPP+ attenuated oxygen consumption and, when combined with hypoxic injury, depolarized mitochondrial membranes in hepatocytes. TPP+ induces systemic responses associated with oxidative stress and worsening pathologies in animals. Caution should be exercised when employing TPP+ for therapeutics.