Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy characterized by a median survival rate of approximately six months. While genetic profiling has uncovered common mutations in PDAC, developing targeted therapeutic strategies remains challenging. SMAD4 is frequently mutated or deleted in 30-55% of PDAC patients and correlates with poor survival rates. Such mutations frequently result in loss-of-function, thereby disrupting normal cell cycle regulation and contributing to tumorigenesis. Therefore, translating SMAD4 genotype into actionable targets are highly desired for therapeutic innovation in PDAC. In this study, we performed a SMAD4-focused oncogenic protein-protein interaction (oncoPPI) network mapping and revealed a direct physical interaction between SMAD4 and NFATc1. We found that SMAD4 interacts with NFATc1 in a TGF-independent and NFATc1 phosphorylation-dependent manner. Further, SMAD4 sequesters NFATc1 in cytoplasm and inhibits NFATc1 transcriptional activity. In PDAC cells, SMAD4-loss releases its inhibitory activity on NFATc1, activates NFATc1 transcriptional activity which drives STAT3 mRNA and protein upregulation. Pharmacological profiling identified multiple STAT3 inhibitors selectively inhibit the growth of SMAD4-loss PDAC cells. These results suggested a rewired SMAD4-NFATc1-STAT3 axis and targeting STAT3 as a potential therapeutic strategy in SMAD4-loss PDAC.