Newborns show physiological differences in low- and high-altitude settings of Ecuador; those differences are especially relevant because most important cities in Ecuador are located at high altitude, above 2500 m. This study is an epidemiological, observational, and cross-sectional research performed at San Francisco Hospital in Quito (at 2850 m) and General Hospital in Manta (at 6 m) in the Manabí province. We studied 204 full-term newborns, healthy without any prenatal comorbidities, singleton pregnancy, mestizos, and born of healthy parents born. We found significant differences between the values of red blood cells (RBC), leucocytes, hematocrit, and hemoglobin. There was a difference of 27% more in RBC, 3% at hematocrit, and 0.4 g at hemoglobin in the high-altitude cohort. The leucocyte difference is 1270 cells/µl, which means a difference of 6%. At high-altitude settings, the mean pH was lower than normal values and pO2, pCO2, and HCO3. High-altitude newborns showed RBC of > 4,500,000 cells/µl; leukocytes > 19,000; pO2 ≤ 72 mm Hg; hemoglobin > 17.50 g/dl; and hematocrit > 54%. Both cohorts showed physiological changes of transition to extrauterine life. We observed higher polycythemia, respiratory acidosis, and hypoxemia among high-altitude newborns. High-altitude setting intensifies the physiological changes in hematological and arterial blood gases parameters.