AMPK, an energy-sensing enzyme, counteracts energy depletion by stimulation of energy production and limitation of energy utilisation. Upon energy depletion, erythrocytes undergo suicidal death or eryptosis, triggered by increase in cytosolic Ca²⁺ ([Ca²⁺]_i) and characterized by cell shrinkage and PS exposure at the erythrocyte surface. The present study explored whether AMPK participates in the regulation of eryptosis. Western blotting and confocal microscopy disclosed AMPK expression in erythrocytes. Glucose removal increased [Ca²⁺]_i, decreased cell volume and increased PS exposure. AMPK-inhibitor compound C did not significantly modify eryptosis under glucose-replete conditions but significantly augmented the eryptotic effect of glucose withdrawal. Increase in [Ca²⁺]_i by Ca²⁺ ionophore ionomycin triggered eryptosis, an effect blunted by AMPK activator AICAR. As compared to erythrocytes from wild type littermates (ampk^+/+), erythrocytes from AMPKa1-deficient mice (ampk^-/-) were significantly more susceptible to the eryptotic effect of energy depletion. ampk^-/- mice were anemic and suffered from severe splenomegaly again pointing to enhanced erythrocyte turnover. The observations disclose a critical role of AMPK in the survival of circulating erythrocytes.