The poor clinical outcome in pancreatic ductal adenocarcinoma (PDA) is attributed to intrinsic chemoresistance and a growth-permissive tumor microenvironment. Conversion of quiescent to activated pancreatic stellate cells (PSCs) drives the severe stromal reaction that characterizes PDA. Here, we reveal that the vitamin D receptor (VDR) is expressed in stroma from human pancreatic tumors and that treatment with the VDR ligand calcipotriol markedly reduced markers of inflammation and fibrosis in pancreatitis and human tumor stroma. We show that VDR acts as a master transcriptional regulator of PSCs to reprise the quiescent state, resulting in induced stromal remodeling, increased intratumoral gemcitabine, reduced tumor volume, and a 57% increase in survival compared to chemotherapy alone. This work describes a molecular strategy through which transcriptional reprogramming of tumor stroma enables chemotherapeutic response and suggests vitamin D priming as an adjunct in PDA therapy. Display omitted Display omitted •VDR is a master transcriptional regulator in pancreatic stellate cells•VDR ligands suppress pancreatitis•Stromal VDR activation overcomes chemotherapeutic drug resistance•VDR ligand plus gemcitabine enhances survival in a PDA mouse model The vitamin D receptor transcriptionally reprograms activated pancreatic stellate cells to a quiescent state to suppress pancreatitis as well as sensitize the stroma to conventional chemotherapy.