Atherosclerosis, a complex cardiovascular disease, is a leading cause of mortality and morbidity worldwide. Oxidative stress and inflammation are both involved in the development of atherosclerotic plaque as they increase the biological processes associated with this pathology, such as endothelial dysfunction and macrophage recruitment and adhesion. Atherosclerotic plaque rupture leading to major ischemic events is the result of vulnerable plaque progression, which is a result of the detrimental effect of oxidative stress and inflammation on risk factors for atherosclerotic plaque rupture, such as intraplaque hemorrhage, neovascularization, and fibrous cap thickness. Thus, both are key targets for primary and secondary interventions. It is well recognized that chronic physical activity attenuates oxidative stress in healthy subjects via the improvement of antioxidant enzyme capacities and inflammation via the enhancement of anti-inflammatory molecules. Moreover, it was recently shown that chronic physical activity could decrease oxidative stress and inflammation in atherosclerotic patients. The aim of this review is to summarize the role of oxidative stress and inflammation in atherosclerosis and the results of therapeutic interventions targeting them in both preclinical and clinical studies. The effects of chronic physical activity on these two key processes are then reviewed in vulnerable atherosclerotic plaques in both coronary and carotid arteries.