Since the prehistoric times, at least 60,000 years back as per fossil records, humans have been using natural products, such as plants, animals, microorganisms, and marine organisms, in medicines to alleviate and treat diseases. The use of natural products as medicines must have a great challenge to early humans because when seeking food in forests and hills, early humans often consumed poisonous plants, which led them to vomiting, diarrhea, coma, or other toxic reaction-even death. Subsequently, they were able to develop knowledge about edible plant materials and to use many plants as natural medicines for treatment of diseases and ailments, which are the basis of traditional medicine. Such forms of traditional medicines, namely, traditional Chinese medicine (TCM), Indian Ayurveda, Greek-Arabic Unani, Japanese Kampo, and traditional Korean medicine, known as Sasang constitutional medicine (SCM) have been practiced worldwide for more than thousands of years and have blossomed into the present systems of modern medicines. The advancement of modern technology helped us to evaluate the pharmacology and mechanism of action of many medicinal herbs in treatment of diseases and to use them as cornerstones of modern medicine. In the historic year 1805, German pharmacist Friedrich Serturner isolated morphine from the opium plant, Papaver somniferum L., and laid the foundation of modern medicine. Subsequently, countless active natural molecules, known as phytochemicals have been separated from natural plant and microbial extracts, and many of them have potential anticancer, antihypertensive, hypolipidemic, antiobese, antidiabetic, antiviral, antileishmanial, and antimigraine medicative properties. These phytochemicals, which have evolved over millions of years, have a unique chemical structural diversity, which results in the diversity of their biological actions to alleviate and treat critical human diseases. A group of evidence advocates that a “multidrugs” and “multi-targets” approach would be more effective compared to a “single-drug” and “single-target” approach in the treatment of complex diseases like obesity, diabetes, cardiovascular disease, and cancer. Phytochemicals present in a single herb or in a herbal formulation can function alone or synergistically with other phytochemicals in a “multi-targets” approach to produce desired pharmacological effect in prevention and cure of complex diseases. The optimal efficacy of the herbal/polyherbal extract depends on its correct dosage containing the optimal concentration of bioactive phytochemical (s) and the method of preparing and processing of the herbal/polyherbal composition and the appropriate time of collection of plant parts. Therefore, the research on natural products is a thrust area for future research in drug discovery (Yuan et al. 2016). This chapter summarizes the current progress in the study of the antiobesity and antidiabetic potentials of natural products and their main bioactive phytochemicals, major molecular mechanisms in preventing and treating obesity and diabetes, and their associated complications.