Non-alcoholic fatty liver disease (NAFLD) is a prevalent liver disorder, affecting approximately 25% of the population. Coffee-drinking obese smokers exhibit lower body weights and decreased NAFLD rates, but the reasons behind this remain unclear. Additionally, the effect of nicotine, the main component of tobacco, on the development of NAFLD is still controversial. Our study aimed to explore the possible reasons that drinking coffee could alleviate NAFLD and gain weight, and identify the real role of nicotine in NAFLD of obese smokers. A NAFLD model in mice was induced by administering nicotine and a high-fat diet (HFD). We recorded changes in body weight and daily food intake, measured the weights of the liver and visceral fat, and observed liver and adipose tissue histopathology. Lipid levels, liver function, liver malondialdehyde (MDA), superoxide dismutase (SOD), serum inflammatory cytokine levels, and the expression of hepatic genes involved in lipid metabolism were determined. Our results demonstrated that nicotine exacerbated the development of NAFLD, and caffeine had a hepatoprotective effect on NAFLD. The administration of caffeine could ameliorate nicotine-plus-HFD-induced NAFLD by reducing lipid accumulation, regulating hepatic lipid metabolism, alleviating oxidative stress, attenuating inflammatory response, and restoring hepatic functions. These results might explain why obese smokers with high coffee consumption exhibit the lower incidence rate of NAFLD and tend to be leaner. It is essential to emphasize that the detrimental impact of smoking on health is multifaceted. Smoking cessation remains the sole practical and effective strategy for averting the tobacco-related complications and reducing the risk of mortality.