Mesoamerica is the center of origin of a great number of food crops that nowadays are part of a healthy diet. Pre-Columbian civilizations utilized more than 90% of these foods as ingredient or in main dishes, as well as for remedies and religious ceremonies. Since several years ago, Mesoamerican foods have been recognized by their outstanding concentration of bioactive compounds, including, phenolic compounds, pigments, essential fatty acids, amino acids, peptides, carbohydrates and vitamins, which provide a great number of health benefits. As a result of their unique composition, these ancient crops have several positive effects, such as hypoglycemic, antioxidant, anti-obesity, anti-inflammatory, anti-ageing, neuroprotective, anti-diarrheal, and anti-hypercholesterolemic capacity. Hence, this review is focused mainly in the anti-obesity and antioxidant potential of some of the most cultivated, harvested, as well as commercialized and consumed, food crops native of Mesoamerica, like, nopal and its fruit (Opuntia ficus indica spp.), chia (Salvia hispanica L.), pumpkin (Cucurbita spp.) and cacao (Theobroma cacao).