KRAS is the most frequently mutated oncogene in human cancer and drives over 90% of pancreatic ductal adenocarcinoma (PDAC). KRAS inhibitors such as MRTX1133 have demonstrated promising, but ultimately limited efficacy in PDAC due to adaptive resistance. AMPK, a central regulator of cellular energy homeostasis, is traditionally viewed as tumor-suppressive, yet it can support survival under metabolic stress by promoting catabolic programs and inhibiting apoptosis. As loss of ATP accompanies oncogene inhibition in various cancers, we hypothesized that AMPK functions as an adaptive resistance mechanism to KRAS inhibition. To test this, we investigated the effects of the selective AMPK inhibitor BAY-3827 in combination with the KRAS-G12D inhibitor MRTX1133. In human HPAC and murine FC1199 PDAC cells, MRTX1133 rapidly induced AMPK phosphorylation. Similarly, in vivo treatment of Kras^G12D;Trp53^-/- autochthonous tumors with MRTX1133 revealed increased AMPK signaling. While BAY-3827 alone had minimal impact on PDAC growth in vitro, its combination with MRTX1133 markedly suppressed proliferation and viability, and enhanced apoptosis. Dual inhibition of KRAS and AMPK re-wired PDAC metabolism, characterized by reduced basal glycolysis and altered mitochondrial respiration. [U-13C]-glucose and [U-13C]-glutamine tracing with targeted GC-MS metabolomics revealed that combined AMPK and KRAS inhibition disrupted de novo serine and cysteine synthesis, suppressed pyruvate carboxylation (PC flux) and reversed the MRTX1133-induced increase in reductive glutamine metabolism. This metabolic rewiring restored PDH-dependent oxidative TCA flux and coincided with a synergistic loss of 4F2hc/xCT amino acid transporters, collectively revealing that AMPK enables PDAC cells to maintain anaplerosis and redox balance during KRAS inhibition. To directly test the requirement of AMPK for tumor survival during KRAS-G12D inhibition, we generated CRISPR-Cas9 knockouts of the AMPKα1/α2 catalytic subunits in both HPAC and FC1199 cells. AMPK loss enhanced the efficacy of MRTX1133 both in vitro and in vivo. Together, these data identify AMPK activation as an adaptive resistance mechanism to KRAS inhibition and highlight AMPK as a potential therapeutic target to improve the durability of oncogene-specific therapies.