Electronic cigarettes (e-cigarettes) have gained popularity; however, evidence for their safety with chronic use is lacking. Acute e-cigarette exposure induces systemic oxidative stress in users and contributes to vascular endothelial dysfunction through reduction in nitric oxide (NO). Polyphenols, abundant in blackberries (BL), mitigate cardiovascular damage. We aimed to determine whether BL was protective against e-cigarette-induced cardiopulmonary detriments. Mice were fed a diet supplemented with or without 5% freeze-dried BL (w/w) for 16 weeks. E-cigarette exposure (1 h, 5 days per week) began at week 4. Additionally, human microvascular endothelial cells (HMVECs) were treated with BL polyphenol extract (200 μg mL-1) and e-cigarette condensate (0.5% v/v). Twelve weeks of e-cigarette exposure induced multi-organ oxidative stress. E-cigarette exposure increased expression of pro-oxidant enzymes in the endothelium resulting in increased superoxide production diminishing NO bioavailability. Additionally, e-cigarettes reduced the phosphorylation of endothelial NO synthase, contributing to decreases in NO. Mice supplemented with BL were protected against decreases in NO and BL pre-treatment in vitro reduced superoxide production. However, BL was not able to attenuate oxidative stress responses in the heart or lungs. These studies demonstrate the contribution of e-cigarettes to vascular pathologies through an increase in superoxide-producing enzymes and the ability of BL polyphenols to mitigate these deleterious effects in the vasculature. Further studies should explore the role of polyphenol-rich foods in protecting against cardiopulmonary conditions induced by chronic e-cigarette use and explore their use in the recovery period post-e-cigarette cessation to properly align with current public health messaging.