SMAD4, a central mediator of the TGF-β signaling pathway, plays a critical role in regulating cellular processes such as proliferation, differentiation, and apoptosis. While SMAD4’s canonical functions within TGF-β signaling are well-established, its non-canonical, TGF-β-independent roles remain poorly understood, particularly in the context of disease biology. Here, we investigate SMAD4’s TGF-β-independent functions by identifying and characterizing its protein–protein interaction network. Using pancreatic ductal adenocarcinoma as a model system, we performed a SMAD4-focused oncogenic protein–protein interaction mapping and uncovered a novel interaction between SMAD4 and NFATc1. We demonstrated that SMAD4 binds to NFATc1 in a phosphorylation-dependent but TGF-β-independent manner, sequestering NFATc1 in the cytoplasm and inhibiting its transcriptional activity. The absence of this interaction in SMAD4-deficient PDAC cells is associated with the activation of NFATc1 transcriptional programs and upregulation of STAT3 at both mRNA and protein levels. Pharmacological profiling revealed multiple STAT3 inhibitors with selective efficacy against SMAD4-deficient PDAC cells in vitro, highlighting a potential therapeutic vulnerability. These findings identify a previously uncharacterized SMAD4–NFATc1 regulatory complex and establish its biological significance in regulating NFATc1-driven transcriptional programs, such as STAT3, providing critical insights into SMAD4’s TGF-β-independent functions and uncovering new opportunities for therapeutic intervention in SMAD4-deficient contexts.