Obesity represents one of the most important public health challenges of the 21st century and is characterized by a multifactorial etiology in which environmental, behavioral, metabolic, and genetic factors work together. Despite the rapid increase in prevalence of obesity in the last decades, especially in children, it remains a preventable disease. To battle obesity a multisector approach promoting healthier lifestyle in terms of physical activity and nutrition is needed. Specifically, biologically active dietary compounds, as polyphenols, are able to modulate the expression of genes involved in the development and progression of obesity and its comorbidities as demonstrated by multiple studies using different obesity models. However, human studies focusing on the transcriptomic modulation by polyphenols in obese patients are still limited and do not often recapitulate the results obtained in preclinical setting likely due to the underestimation of some variables such as bioavailability, dose and form (native vs. metabolized) of polyphenols used. The aim of this review is to summarize the state-of-art of nutrigenomic in vitro, in vivo and ex vivo studies as well as clinical trials based on dietary polyphenols to fight obesity. We also critical discuss the variables to be considered to fill the gap between preclinical and clinical settings.