Oxidative stress has been described as one of the main drivers of intracellular damage and metabolic disorders leading to metabolic syndrome, a major health problem worldwide. In particular, free radicals alter lipid metabolism and promote lipid accumulation in the liver, existing in the hepatic facet of metabolic syndrome, the metabolic dysfunction-associated steatotic liver disease (MASLD). Recent literature has highlighted how nicotine, especially if associated with a high-fat diet, exerts a negative effect on the induction and progression of MASLD by upregulating inflammation and increasing oxidative stress, abdominal fat lipolysis, and hepatic lipogenesis. Moreover, considerable evidence shows the central role of intestinal dysbiosis in the pathogenesis of MASLD and the impact of nicotine-induced oxidative stress on the gut microbiome. This results in an intricate network in which oxidative stress stands at the intersection point between gut microbiome, nicotine, and MASLD. The aim of this review is to delve into the molecular mechanisms linking tobacco smoking and MASLD, focusing on nicotine-induced microbiota modifications and their impact on MASLD development.