Brain Type Glycogen Phosphorylase (PYGB) has been revealed to participate in the progression of multiple human cancers. Nevertheless, the clinical significance and biological function of PYGB in pancreatic ductal adenocarcinoma (PAAD) remains unclarified. This study first analyzed the expression pattern, diagnostic value, and prognostic significance of PYGB in PAAD using the TCGA database. Subsequently, western blot assessed the protein expression of genes in PAAD cells. The viability, apoptosis, migration, and invasion of PAAD cells were assessed by CCK-8, TUNEL, and Transwell assays. Finally, in vivo experiment evaluated the effect of PYGB on PAAD tumor growth and metastasis. Through our investigation, it was revealed that PYGB had extremely high expression in PAAD and predicted a worse prognosis in patients with PAAD. Besides, the aggressiveness of PAAD cells could be suppressed or enhanced by depleting or supplementing PYGB. In addition, we demonstrated that METTL3 enhanced the translation of PYGB mRNA in an mA-YTHDF1-dependent manner. Moreover, PYGB was revealed to regulate the malignant behaviors of PAAD cells by the mediation of the NF-κB signaling. Finally, PYGB depletion suppressed the growth and distant metastasis of PAAD in vivo. To conclude, our results indicated that METTL3-mediated mA modification of PYGB exerted the tumor-promotive effect on PAAD through NF-κB signaling, suggesting PYGB is a potential therapeutic target in PAAD.