Little attention has been devoted to the role of HLA‐G gene and molecule on parasitic disorders, and the available studies have focused on malaria, African and American trypanosomiasis, leishmaniosis, toxoplasmosis and echinococcosis. After reporting a brief description regarding the role of the cells of innate and adaptive immune system against parasites, we reviewed the major features of the HLA‐G gene and molecule and the role of HLA‐G on the major cells of immune system. Increased levels of soluble HLA‐G (sHLA‐G) have been observed in patients presenting toxoplasmosis and in the active phase of echinococcosis. In addition, increased sHLA‐G has also been associated with increased susceptibility to malaria and increased susceptibility to develop human African trypanosomiasis (HAT). In contrast, decreased membrane‐bound HLA‐G has been reported in placenta of patients infected withPlasmodium falciparumand in heart and colon of patients presenting Chagas disease. The 3′ untranslated region of theHLA‐Ggene has been the main focus of studies on malaria, HAT and Chagas disease, exhibiting distinct patterns of associations. Considering that HLA‐G is an immune checkpoint molecule, inhibiting the activity of several cells of the immune system, the excessive neoexpression and the increased sHLA‐G levels together with the decreased constitutive tissue expression of membrane‐bound HLA‐G may be detrimental to the host infected with parasite agents.