Fusarium head blight (FHB) is a devastating disease in wheat worldwide. It not only results in yield loses but also in DON accumulation in infected grains. DON also facilitates the pathogen colonization and spread of FHB symptoms in disease development. UDP-glycosyltransferase enzymes (UGTs) are known to contribute detoxification and enhance FHB resistance by glycosylating DON into DON-3-Glucoside (D3G) in wheat. In this study we carried out a genome-wide analysis of family-1 UDP glycosyltransferases in wheat based on the PSPG conserved box that resulted in the identification of 179 putative UGT genes. The expression of many UGT genes was up-regulated after Fusarium graminearum inoculation, and one of a novel gene named TaUGT6 was further characterized. TaUGT6 was strongly induced by F.g or DON in FHB-resistant cultivar Sumai3. The purified TaUGT6 protein was used to do the enzyme activity assay, and the results showed that it was able to convert DON into D3G. The promoter deletion analysis showed that sequences between 431 and 1200 bp upstream of the transcriptional start site were required for DON-induced expression. Furthermore, the overexpression of TaUGT6 in Arabidopsis conferred enhanced tolerance when grown on agar plates that contain DON, suggesting its critical role in the resistance to FHB and DON accumulation. Overall, this study gave a useful insight into the genome-wide analysis of Family-1 UDP glycosyltransferases and identified a novel UGT gene for FHB resistance in wheat.