Metabolic reprogramming contributes to oncogenesis, tumor growth, and treatment resistance in pancreatic ductal adenocarcinoma (PDAC). Here we report the effects of (R,S′)-4′-methoxy-1-naphthylfenoterol (MNF), a GPR55 antagonist and biased β₂-adrenergic receptor (β₂-AR) agonist on cellular signaling implicated in proliferation and metabolism in PDAC cells. The relative contribution of GPR55 and β₂-AR in (R,S′)-MNF signaling was explored further in PANC-1 cells. Moreover, the effect of (R,S′)-MNF on tumor growth was determined in a PANC-1 mouse xenograft model. PANC-1 cells treated with (R,S′)-MNF showed marked attenuation in GPR55 signal transduction and function combined with increased β₂-AR/Gα_s/adenylyl cyclase/PKA signaling, both of which contributing to lower MEK/ERK, PI3K/AKT and YAP/TAZ signaling. (R,S′)-MNF administration significantly reduced PANC-1 tumor growth and circulating l-lactate concentrations. Global metabolic profiling of (R,S′)-MNF-treated tumor tissues revealed decreased glycolytic metabolism, with a shift towards normoxic processes, attenuated glutamate metabolism, and increased levels of ophthalmic acid and its precursor, 2-aminobutyric acid, indicative of elevated oxidative stress. Transcriptomics and immunoblot analyses indicated the downregulation of gene and protein expression of HIF-1α and c-Myc, key initiators of metabolic reprogramming in PDAC. (R,S′)-MNF treatment decreased HIF-1α and c-Myc expression, attenuated glycolysis, shifted fatty acid metabolism towards β-oxidation, and suppressed de novo pyrimidine biosynthesis in PANC-1 tumors. The results indicate a potential benefit of combined GPR55 antagonism and biased β₂-AR agonism in PDAC therapy associated with the deprogramming of altered cellular metabolism.