Two human hemoglobin (Hb) variants, Hb C and Hb S, are known to protect against Plasmodium falciparum malaria and have evolved repeatedly in malaria endemic areas. Both aggregate to insoluble crystals (Hb C) or polymers (Hb S) under certain physiological conditions, impair parasite growth and may facilitate retention of infected red blood cells (RBCs) in the spleen. Given the profound effects of parasites on host evolution in general, and RBC Hb concentrations close to the solubility limit throughout vertebrates, similar mechanisms may operate in non-human vertebrates. Here we show exercise-induced, profound in vivo Hb polymerization in RBCs of the Gulf toadfish. Hb aggregation was closely associated with the extent of plasma acidosis, fully reversible and without any signs of haemolysis or anemia. Our literature analysis suggests that aggregation prone Hbs may be relatively old, evolved multiple times in non-human vertebrates, show enhanced aggregation during hemoparasite infections and can be uncovered in vivo by splenectomy. We suggest that they are the result of on-going selection pressure against RBC parasites. Comparative studies of these long established systems may provide valuable insights into hemoparasite susceptibility and reservoir potential of livestock and companion animals, but also into human malaria and sickle cell disease.