Cells constantly produce oxidizing species because of their metabolic activity, which is counteracted by the continuous production of antioxidant species to maintain the homeostasis of the redox balance. A deviation from the metabolic steady state leads to a condition of oxidative stress. The source of oxidative species can be endogenous or exogenous. A major exogenous source of these species is tobacco smoking. Oxidative damage can be induced in cells by chemical species contained in smoke through the generation of pro-inflammatory compounds and the modulation of intracellular pro-inflammatory pathways, resulting in a pathological condition. Cessation of smoking reduces the morbidity and mortality associated with cigarette use. Next-generation products (NGPs), as alternatives to combustible cigarettes, such as electronic cigarettes (e-cig) and tobacco heating products (THPs), have been proposed as a harm reduction strategy to reduce the deleterious impacts of cigarette smoking. In this review, we examine the impact of tobacco smoke and MRPs on oxidative stress in different pathologies, including respiratory and cardiovascular diseases and tumors. The impact of tobacco cigarette smoke on oxidative stress signaling in human health is well established, whereas the safety profile of MRPs seems to be higher than tobacco cigarettes, but further, well-conceived, studies are needed to better understand the oxidative effects of these products with long-term exposure.