The ethnopharmaceutical approach is important for the discovery and development of natural product research and requires a deep understanding not only of biometabolites discovery and profiling but also of cultural and social science. For millennia, epigeous macrofungi (mushrooms) and hypogeous macrofungi (truffles) were considered as precious food in many cultures based on their high nutritional value and characterized pleasant aroma. In African and Middle Eastern cultures, macrofungi have long history as high nutritional food and were widely applied in folk medicine. The purpose of this review is to summarize the available information related to the nutritional and medicinal value of African and Middle Eastern macrofungi and to highlight their application in complementary folk medicine in this part of the world.