Epidemiological and animal experimental studies suggest an association between gestational cholestasis and intrauterine growth restriction (IUGR). Here, we explored the mechanism through which gestational cholestasis induced IUGR. To establish gestational cholestasis model, pregnant mice were subcutaneously injected with 17α‐Ethynylestradiol (E2) on gestational day 13 (GD13)–GD17. Some pregnant mice were intraperitoneally injected with 4μ8C on GD13–GD17. The results found that the apoptosis of trophoblast cells was elevated in placentas of mice with gestational cholestasis and in deoxycholic acid (DCA)‐treated human trophoblast cell lines and primary mouse trophoblast cells. Correspondingly, the levels of placental cleaved caspase‐3 and Bax were increased, while placental Bcl2 level was decreased in mice with gestational cholestasis and in DCA‐treated trophoblast cells. Further analysis found that placental IRE1α pathway was activated in mice with gestational cholestasis and in DCA‐treated trophoblast cells. Interestingly, 4μ8C, an IRE1α RNase inhibitor, significantly inhibited caspase‐3 activity and apoptosis of trophoblast cells in vivo and in vitro. Importantly, 4μ8C rescued gestational cholestasis‐induced placental insufficiency and IUGR. Furthermore, a case–control study demonstrated that placental IRE1α and caspase‐3 pathways were activated in cholestasis cases. Our results provide evidence that gestational cholestasis induces placental insufficiency and IUGR may be via triggering IRE1α‐mediated apoptosis of placental trophoblast cells.