Non-small cell lung cancer (NSCLC), the most common type of lung cancer, is a leading cause of cancer death. G protein-coupled receptor 54 (GPR54) plays a role in cancer development by interacting with its endogenous ligand kisspeptin encoded by the KISS1 gene. However, the role of GPR54 in NSCLC development is not yet fully understood. Here, we demonstrate that GPR54 regulates NSCLC development via dopa decarboxylase (DDC). A mutant Kras-driven mouse lung cancer model revealed that adenoviral CMV-Cre-mediated Gpr54 deletion attenuated NSCLC development. Both Gpr54 deletion in mouse NSCLC tissues and GPR54 knockdown in human NSCLC cell lines caused apoptotic cell death. In addition, GPR54 regulation of NSCLC cell proliferation involves both the Gα_q/11/AKT and β-arrestin/ERK signaling pathways. RNA sequencing revealed that Gpr54 deletion altered a gene set related to glycolysis and genotype-dependently regulated Ddc gene expression. Moreover, the regulation of glycolysis and DDC expression by GPR54 was dependent on the Gα_q/11/PI3K/AKT/mTOR signaling pathway. Phosphoprotein arrays further revealed that DDC regulated NF-κB phosphorylation in NSCLC cells. Consistently, DDC regulated both NSCLC cell proliferation in vitro and tumor growth in vivo. Overall, our findings suggest that GPR54 could be a diagnostic marker for NSCLC and that therapeutics targeting GPR54 signaling may be useful for treating NSCLC.