Severe preeclampsia (severe PE) is a serious pregnancy complication associated with placental dysfunction, hypoxia, and an imbalance of angiogenic factors such as Soluble Fms-Like Tyrosine Kinase 1 (sFLT1). This study aims to identify significant Differentially Expressed Genes (DEGs) under hypoxic conditions, determine hub genes, and evaluate the therapeutic potential of phenolic compounds using an in silico approach. Shared DEGs analysis was conducted using Gene Expression Omnibus (GEO) datasets with the GEO2R method, and hub gene identification was performed using Cytoscape. Molecular docking simulations were carried out to assess the interaction of phenolic compounds with the target proteins of the identified hub genes. The analysis identified FLT1, VEGFC, EGFR, and FGF1 as key genes involved in the HIF-1, MAPK, and PI3K-Akt signaling pathways. Cross-validation using a neural network based on these four DEGs showed 100% sensitivity and specificity in the hypoxic vs. normoxic Human Trophoblast 8 (HTR8) cell model. In severe PE patient placentas, the sensitivity was 93.3% and the specificity 92.9%. Molecular docking results suggest salvianolic acid (rerank score-96.97 kJ/mol vs.-92.17 kJ/mol for the native ligand) as a potential EGFR inhibitor, predicted to reduce FLT1 expression. Meanwhile, baicalin (rerank score-136.70 kJ/mol vs.-129.33 kJ/mol for the native ligand) is predicted to directly inhibit FLT1 activity. This study highlights FLT1, VEGFC, EGFR, and FGF1 as potential biomarkers for severe PE diagnosis and supports the development of phenolic compounds as molecular-based therapies. Further in vitro and in vivo validation is required to confirm these findings. © 2025 Suryandari et al.