Pyruvate kinase is an important enzyme of glycolytic pathway that catalyzes the last step of this pathway. In human erythrocytes, there is no mitochondrion hence glycolytic pathway is the most important source of energy generation. In vitro, in vivo, and case control studies suggested that pyruvate kinase deficiency provides resistance against P. falciparum caused malaria. Erythrocytes having pyruvate kinase deficiency are less permissive for P. falciparum infection. The gene that encodes pyruvate kinase exhibits excessive diversity in malaria endemic region such as sub-Saharan Africa. Pyruvate kinase variants possibly affect frequency and intensity of malaria episodes in population exist in in malaria endemic regions. Malaria, a strong selective force shapes the genome region of pyruvate kinase gene. Co-distribution of malaria and pyruvate kinase deficiency has been reported in malaria endemic regions. High incidence of pyruvate kinase deficiency appears to maintain in malaria endemic regions as a protective mechanism against malaria.