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Endogenous ouabain (EO) is a steroid hormone secreted by the adrenal glands, usually associated with adverse cardiovascular effects. However, recent studies have highlighted its possible role in blood pressure control and in cardio-renal damage, and it seems to be involved in the adaptive response to hypoxia. The aim of this study is to detect the EO in human and animal models of hypoxia. We collected blood samples from seven competitive elite apnea divers, 11 noncompetitive elite apnea divers, and 26 healthy control subjects. Animal blood samples were collected from 16 common bottlenose dolphins (Tursiops truncatus), two phocids and two otariids kept under human care, and 11 wild loggerhead sea turtles (Caretta caretta) hosted in two rescue centers. We measured EO plasma concentrations with a Scintillation Proximity Assay. In elite apnea divers and healthy control subjects, EO plasma concentrations were positively correlated to weight (p < 0.05). Elite apnea divers showed statistically significant (p < 10-6) higher EO plasma concentrations compared to healthy subjects without any diving experience or experience in other sports activities involving breath-holding. In dolphins, EO plasma concentrations were positively correlated to age, total length, and weight (p < 0.05). In loggerhead sea turtles, EO plasma concentrations were negatively correlated to total length and weight (p < 0.05). In pinnipeds, correlation analysis was not performed due to the small number of animals. Herein, we demonstrate, for the first time, that different taxa, phylogenetically distant from each other and which perform apneas without reporting neurological damages, express EO. Our findings, although preliminary, are in line with the recently emerging hypothesis on a possible role of EO in the adaptive response to hypoxia and represent a helpful hint for future investigations aimed to identify novel molecules useful to treat very disabling pathological conditions such as idiopathic pulmonary arterial hypertension or obstructive sleep apnea.