Abscisic acid (ABA) is a hormone with a long evolutionary history, dating back to the earliest living organisms, of which modern (ABA-producing) cyanobacteria are likely descendants, which existed long before the separation of the plant and animal kingdoms, with a conserved role as signals regulating cell responses to environmental challenges. In mammals, along with the anti-inflammatory and neuroprotective function of ABA, nanomolar ABA regulates the metabolic response to glucose availability by stimulating glucose uptake in skeletal muscle and adipose tissue via an insulin-independent mechanism and increasing metabolic energy production and also dissipation in brown and white adipocytes. Chronic ABA intake of micrograms per Kg body weight improves blood glucose, lipids, and morphometric parameters (waist circumference and body mass index) in borderline subjects for prediabetes and metabolic syndrome. This review summarizes the most recent in vitro and in vivo data obtained with nanomolar ABA, the involvement of the receptors LANCL1 and LANCL2 in the hormone’s action, and the importance of mammals’ endowment with two distinct hormones governing the metabolic response to glucose availability. Finally, unresolved issues and future directions for the clinical use of ABA in diabetes are discussed.