Long noncoding RNAs (lncRNAs) are associated with tumorigenesis and linked to altered metabolism. Our previous studies have identified an oncogenic function of lncRNA Linc00173 in small cell lung cancer (SCLC), while the detailed mechanisms remain to be fully clarified. We show that Linc00173 plays a critical role for chemoresistance in SCLC through reprogramming glucose metabolism. By phosphorylating Y-Box Binding Protein 1 (YB1), Linc00173 stimulates the translation of YB1 bound glucose metabolic enzymes HK2 and G6PD, which activates glycolysis and the pentose phosphate pathway (PPP). The expression levels of Linc00173 and HK2/G6PD show a positive correlation in 46 tissue samples from SCLC patients. Furthermore, we demonstrated that the inhibitors of HK2 and G6PD, 3-BrPA and RRx-001, exhibit a synergistic antitumor effect with chemotherapy both in vitroand in vivo,including a PDX model. For the first time, we identified the mechanism of Linc00173/YB1 axis-induced glucose metabolic rewiring in SCLC, indicating that glucose metabolic enzymes HK2 and G6PD may be potential therapeutic targets for SCLC treatments.