Tramadol and alcohol are among commonly abused drugs. Although there are potential dangers reported upon their mixing, there are no previous reports describing this mixture's effects on the cardiovascular system (CVS). The aim was to study the effects of mixed alcohol and tramadol on the CVS of adult male rats. Fifty rats were divided into four groups: control, tramadol‐treated group, alcohol‐treated, and coadministration groups. Tramadol caused a significant increase in creatine kinase MB, troponin I, malondialdehyde, protein carbonyl, 8‐hydroxy‐2′‐deoxyguanosine, and a significant decrease in total antioxidant capacity with histological alterations in sections of the heart and aorta and a significant increase in the area% of collagen fibers while there was a nonsignificant difference in body weight, heart weight, heart weight/body weight ratio, lipid profile, tissue tumor necrosis factor‐α and interferon‐γ, intermediate microfilament proteins (IFPs) {desmin, vimentin, connexin43} gene expression, mean area% of elastic fibers in aortic tissue and osteopontin expression in cardiac and aortic tissue. Alcohol treatment caused a significant change in all the measured parameters and more damage in histological sections. The changes were highest in the coadministration group. There was a strong positive correlation between the area% of collagen fibers and vimentin gene expression, and the area% of osteopontin expression was positively correlated to connexin43 in cardiac and vascular tissue. Tramadol causes CVS injury mainly through oxidative stresses, while the alcohol effect is multifactorial; mixing both aggravates CVS injury. The study also highlights the role of IFPs and osteopontin‐expression in inducing injury.