The prevalence and incidence of obesity and the comorbidities linked to it are increasing in the world population. Current therapies for obesity and associated pathologies have proven to cause a broad number of adverse effects and often, they are overpriced or not affordable for all patients. Among the alternatives currently available, natural bioactive compounds stand out. These are frequently contained in pharmaceutical presentations, nutraceutical products, supplements, or functional foods. The clinical evidence for these molecules is increasingly solid, among which epigallocatechin-3-gallate, ellagic acid, resveratrol, berberine, anthocyanins, probiotics, carotenoids, curcumin, silymarin, hydroxy citric acid, and α-lipoic acid stand out. The molecular mechanisms and signaling pathways of these molecules have been shown to interact with the endocrine, nervous, and gastroenteric systems, as well as regulate the expression of multiple genes and, therefore, proteins involved in starvation-satiety processes, activation of brown adipose tissue, increased lipolysis, decreased lipogenesis, and inflammation, beneficial changes in metabolism and improved insulin sensitivity. This review provides a comprehensive view of nature-based therapeutic options to address the increasing prevalence of obesity. It offers a valuable perspective for future research and subsequent clinical practice, addressing everything from the molecular, genetic, and physiological bases to the clinical study of the bioactive compound.