Hexokinase 2 (HK2) is widely distributed in various tissues, particularly showing significantly elevated expression levels in tumor tissues. As the initial rate-limiting enzyme in the glycolysis process, HK2 is believed to directly participate in the metabolic reprogramming of tumor cells. This phenomenon, known as the "Warburg effect," provides the energy and substances necessary for the rapid proliferation, growth, and division of tumor cells. Furthermore, by enhancing glycolysis, HK2 exerts its influence on various metabolic pathways in tumor cells, such as pentose phosphate metabolism, glutamine metabolism, serine metabolism, and glycine metabolism, thereby playing a role in the occurrence and development of cancer. Therefore, HK2 represents a promising target for cancer therapy. Simultaneously, natural products with effects on inhibiting the expression or activity of HK2, have already been discovered to exhibit significant anticancer potential. Flavonoids, pentacyclic triterpenoids, phenolic compounds, and lignans constitute the majority of these natural products, directly inhibiting HK2 or indirectly downregulating it through protein kinase B (AKT), hypoxia-inducible factor 1 alpha (HIF-1α), and c-Myc signaling pathways. However, several challenges remain, such as further screening for natural products that directly target and inhibit HK2, optimizing the selection of natural product inhibitors for HK2, and elucidating the molecular mechanisms by which natural products indirectly inhibit HK2. In conclusion, the potential of targeting HK2 for cancer therapy is promising, and with these challenges addressed, natural products inhibiting HK2 will play an even greater role in the fight against cancer.