Metabolic reprogramming is fundamental to biological homeostasis, enabling cells to adjust metabolic routes after sensing altered availability of fuels and growth factors. ULK1 and ULK2 represent key integrators that relay metabolic stress signals to the autophagy machinery. Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1). Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels. These results identify ULK1/2 as a bifurcate-signaling node that sustains glucose metabolic fluxes besides initiation of autophagy in response to nutritional deprivation. Display omitted •ULK1/2 deficiency leads to reduction of glycolysis during nutritional stresses•HK1, PFK1, FBP1, and ENO1 are direct substrates of the ULK1 kinase•ULK1 regulates activities of glycolytic enzymes and sustains glycolysis and PPP flux•ULK1/2 reprogram glucose metabolic fluxes independently of autophagy Metabolic reprogramming underlies adaptive responses to various stresses. Li et al. discover that the autophagy-initiating kinases ULK1/2 also phosphorylate multiple glycolytic enzymes to sustain glycolysis and increase the proportion of glucose flux to the pentose phosphate pathway during nutritional stresses.