Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive neoplastic diseases of the pancreas with fatal proliferation and metastasis and no medicine available for treatment. From an Antarctica sponge-derived fungus, <i>Aspergillus insulicola</i> HDN151418, four new nitrobenzoyl sesquiterpenoids, namely, insulicolides D-G (<b>1</b>-<b>4</b>), were isolated. Compounds <b>3</b> and <b>4</b> exhibited selective inhibition against human PDAC cell lines. Further studies indicated that compound <b>4</b> could significantly suppress cell proliferation to induce apoptosis and blocked migration and invasion of PDAC cells. Compound <b>4</b> could also avoid resistance and improved the therapeutic effect of the chemotherapy drug gemcitabine. A preliminary mechanism study showed that compound <b>4</b> can significantly inhibit the expression of EGFR and XIAP in PDAC cells. Altogether, <b>4</b> is a potential lead compound for anti-PDAC drug research.