Erythropoietin (EPO) is an endogenous regulator of erythropoiesis and is given exogenously as a replacement therapy for selected red blood cell disorders. In the past years, EPO has been emerging as a multifunctional, cytoprotective cytokine with anti-apoptotic, anti-inflammatory, and immunomodulatory properties. We aimed to evaluate the cytoprotective effect of rhEPO (recombinant human EPO) treatment on a rat model of multiorgan dysfunction induced by thermal injury. rhEPO was administered at 1000 U/kg (i.v.) 5 min prior to induction of injury and significantly reduced multiorgan dysfunction markers (liver, kidney, lung, serum cytokine levels). In the lung, rhEPO reduced: histological signs of tissue injury, inflammatory/injury markers on the bronchoalveolar fluid, neutrophil chemotaxis/infiltration, GSK-3β activation, and apoptosis. Our study showed that erythropoietin has the potential to exhibit pleiotropic cytoprotective effects and that it might be an interesting pharmacological strategy in the modulation of acute lung injury, such as the one associated to severe burn.