Altered metabolism is one of the hallmarks of cancer. The best-known cancer metabolic anomaly is an increase in aerobic glycolysis, which generates ATP and other basic building blocks, such as nucleotides, lipids, and proteins to support tumor cell growth and survival. Epithelial plasticity (EP) programs such as the epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) are evolutionarily conserved processes that are essential for embryonic development. EP also plays an important role during tumor progression toward metastasis and treatment resistance, and new roles in the acceleration of tumorigenesis have been found. Recent evidence has linked EMT-related transcriptomic alterations with metabolic reprogramming in cancer cells, which include increased aerobic glycolysis. More recent studies have revealed a novel connection between EMT and altered glycosylation in tumor cells, in which EMT drives an increase in glucose uptake and flux into the hexosamine biosynthetic pathway (HBP). The HBP is a side-branch pathway from glycolysis which generates the end product uridine-5′-diphosphate-N-acetylglucosamine (UDP-GlcNAc). A key downstream utilization of UDP-GlcNAc is for the post-translational modification O-GlcNAcylation which involves the attachment of the GlcNAc moiety to Ser/Thr/Asn residues of proteins. Global changes in protein O-GlcNAcylation are emerging as a general characteristic of cancer cells. In our recent study, we demonstrated that the EMT-HBP-O-GlcNAcylation axis drives the O-GlcNAcylation of key proteins such as c-Myc, which previous studies have shown to suppress oncogene-induced senescence (OIS) and contribute to accelerated tumorigenesis. Here, we review the HBP and O-GlcNAcylation and their putative roles in driving EMT-related cancer processes with examples to illuminate potential new therapeutic targets for cancer.