Aberrant activation of oncogenic kinases leads to metabolic and translational reprogramming. To maintain energy homeostasis, cancer cells must therefore produce sufficient ATP to meet high-energy demand of hyperactive translational machinery while sustaining translational and metabolic programs that fuel neoplastic growth. We show that biguanide-induced energy stress caused by abrogation of mitochondrial ATP production strongly increases anti-neoplastic efficacy of oncogenic kinase inhibitors (KIs). Biguanides and KIs exert synergistic anti-neoplastic effects across a variety of cancer types, by exerting opposing effects on aerobic glycolysis and reductive glutamine metabolism, while cooperatively rewiring metabolic programs via the mTORC1/4E-BP-dependent translational reprogramming and HIF1α. Translational perturbations mediated by mTORC1/4E-BP axis lead to profound metabolic changes including alterations in serine and asparagine biosynthesis pathways, which are a critical determinant of the sensitivity of cancer cells to KI/biguanide combination. In addition, we show that metabolic reprogramming engendered by 4E-BP-independent reduction in HIF1α levels contributes to the synergistic anti-neoplastic effects between KIs and biguanides. Collectively, these findings delineate cancer-specific metabolic networks that determine the efficacy of KIs.