Mycotoxins are highly dangerous natural compounds produced by various fungi. Enzymatic transformation seems to be the most promising method for detoxification of mycotoxins. This review summarizes current information on enzymes of different classes to convert various mycotoxins. An in-depth analysis of 11 key enzyme mechanisms towards dozens of major mycotoxins was realized. Additionally, molecular docking of mycotoxins to enzymes’ active centers was carried out to clarify some of these catalytic mechanisms. Analyzing protein homologues from various organisms (plants, animals, fungi, and bacteria), the prevalence and availability of natural sources of active biocatalysts with a high practical potential is discussed. The importance of multifunctional enzyme combinations for detoxification of mycotoxins is posed.