Preeclampsia is currently thought to be characterized by placental oxidative stress damage. Hydroxychloroquine is known to have antioxidant effects, but there are fewer studies on hydroxychloroquine in oxidative stress in preeclampsia. The main objective of this study was to investigate the effects of hydroxychloroquine on oxidative stress injury in preeclampsia and its related mechanisms by establishing cellular and animal models. Our study showed that hydroxychloroquine lowered blood pressure and urinary protein, ameliorated placental and renal damage, and improved preeclampsia rat outcomes. Hydroxychloroquine treatment activated the PI3K/AKT/mTOR pathway and inhibited excessive autophagy to ameliorate oxidative stress injury, and these effects were attenuated after application of the PI3K inhibitor LY294002. In summary, hydroxychloroquine may inhibit autophagy by activating the PI3K/AKT/mTOR pathway, which in turn ameliorates oxidative stress injury and improves preeclampsia outcomes. Our study provides a new theoretical basis for hydroxychloroquine application for preeclampsia therapy.