Atherothrombosis is a recurrent complication in APS and SLE patients. Oxidative stress has been suggested as a key player underlying this process. Autoantibodies have been pointed to as the main contributors to abnormality in the oxidative status observed in APS and SLE patients, promoting the increased production of oxidant species and the reduction of antioxidant molecules. This imbalance causes vascular damage through the activation of immune cells, including monocytes, lymphocytes and neutrophils, causing the expression of pro-inflammatory and procoagulant molecules, the formation of neutrophil extracellular traps and the adhesion of these cells to the endothelium; the induction of cellular apoptosis and impaired cell clearance, which in turn enhances autoantibody neogeneration; and cytotoxicity of endothelial cells. This review describes the mechanisms underlying the role of oxidative stress in the pathogenesis of atherothrombosis associated with APS and SLE, focused on the effect of autoantibodies, the different cell types involved and the diverse effectors, including cytokines, procoagulant proteins and their main modulators, such as oxidant/antioxidant species and intracellular pathways in each pathology. We further discuss new therapies aimed at restoring the oxidative stress balance and subsequently to tackle atherothrombosis in APS and SLE.