Pancreatic cancer is one of the most lethal human cancers that currently does not have effective therapies. Novel treatments including nanomedicines and combination therapies are thus urgently needed for these types of deadly diseases. A key feature of pancreatic cancer is its tumor protective dense stroma, which is generated by cancer-associated fibroblasts (CAFs). The interaction between CAFs and pancreatic cancer cells abnormally activates sonic hedgehog (SHH) signaling and facilitates tumor growth, metastasis, and drug resistance. Here, we report that the commercial SHH inhibitor GDC-0449 reverses fibroblast-induced resistance to doxorubicin in Smoothened (SMO)-positive pancreatic cancer cells by downregulating SHH signaling proteins. Importantly, the synergistic combination of GDC-0449 with PEG-PCL-Dox exhibited potent antitumor efficacy in a BxPC-3 tumor xenograft model, whereas single treatments did not significantly inhibit tumor growth. Our findings reveal a potential treatment strategy for fibroblast-enriched pancreatic cancer.