Fusarium head blight (FHB) caused by Fusarium graminearum is a worldwide disease which has destructive effects on wheat production, resulting in severe yield reduction and quality deterioration, and FHB-infected wheat grains are toxic to people and animals due to accumulation of fungal toxins. The resistance mechanism of FHB is quite complex with Type I (resistance to initial infection), II (resistance to disease spread within a spike), III (resistance to mycotoxin accumulation in grains), and IV (resistance to kernel infection). The association of multi-omics with resistance types helped elucidation of the FHB resistance mechanism, and be of interest to wheat pathologists, breeders, geneticists in the field of wheat Fusarium head blight. Here we report the potential resistance mechanisms by linking different resistance types to multi-omics and emphasize the pathways or genes that may play significant roles in the different types of resistance. Among these, the specific accumulation of genes in tricarboxylic acid cycle (TCA), the important role of pathogenesis-related proteins and phytohormone-related pathways may play critical roles in Type I resistance. Cell wall biomolecular composition and phenylpropanoid pathway contribute to type II resistance by thickening the cell wall or inhibiting the activity of the plant cell wall degrading enzymes; Detoxification genes such as UDP-glucuronosyltransferases, ATP-binding cassette transporters, Glutathione S-transferases and cytochromes P450s function in Type III resistance; Inhibition of pathogen alpha-amylase and plant beta-amylase activities may be associated with Type IV resistance to FHB. These pathways and (or) genes could be utilized and manipulated to improve overall FHB resistance in wheat breeding programs by using transgenic approaches, gene editing, or marker assisted selection strategies.