Pre-eclampsia (PE) is a global pregnancy-related disorder that is characterized mainly by impaired migration and invasion of trophoblast cells. Recently, autophagy has been shown to play a vital role in PE. However, the precise regulatory mechanisms underlying the upregulation of autophagy are still unclear. In this study, TP53BP2 expression was significantly upregulated in trophoblasts. Silencing TP53BP2 not only decreases autophagy but also attenuates the progression of PE in rats. Moreover, TP53BP2 expression was positively correlated with systolic blood pressure, diastolic blood pressure and body mass index (BMI) but was negatively correlated with gestational age at delivery and neonatal birth weight. Furthermore, our findings suggest that TP53BP2 enhances autophagy in trophoblasts by promoting the release of Beclin-1 from the Bcl-2/Beclin-1 complex. Additionally, DNMT1 and G9a were found to downregulate TP53BP2 expression through a cooperative reduction in DNA methylation and H3K9me2 enrichment at the promoter region of TP53BP2. More importantly, cooperation between DNMT1 and G9a suppressed the binding of E2F1 at the TP53BP2 promoter, leading to transcriptional inhibition of TP53BP2 in PE trophoblasts. In conclusion, our findings suggest that TP53BP2 promotes autophagy in trophoblasts of preeclamptic placentas through DNA methylation and H3K9me2-mediated transcriptional regulation and may serve as a potential therapeutic target for early-onset PE.