Preeclampsia is a pregnancy complication characterized by high blood pressure and damage to organs such as the liver and kidneys. Despite its severity, the pathophysiology of preeclampsia remains poorly understood, and early diagnosis is a significant challenge. This prospective case-control study aimed to investigate the potential of serum endoglin (sEng), interleukin-6 (IL-6), and interferon gamma (IFN-γ) as diagnostic biomarkers for preeclampsia. The study was conducted at Asaba Specialist Hospital, a tertiary hospital with Antenatal Clinic in Delta State, Nigeria. Sixty participants (30 preeclamptic (on set) and 30 healthy pregnant controls (during clinic) was determined using G*Power Software and were recruited based on inclusion and exclusion criteria after approval was obtained from the Ethical and Research committee of the hospital and informed consent taken from participants. Blood samples were collected and stored at above -20°C until analysis. Statistical analysis was performed using SPSS version 25. The main findings of this study were that sEng, IL-6, and IFN-γ levels were significantly higher in women with preeclampsia compared to controls (p < 0.05). The ratio of sEng, IL-6, and IFN-γ between preeclamptic patients and healthy controls was 4:1, 2:1, and 2:1, respectively. The ROC analysis reveals an excellent diagnostic accuracy of the biomarkers with the area under curve (AUC) of 0.98, 0.99 and 0.99 for sEng, IL-6, and IFN-γ respectively. This demonstrates the potential of serum endoglin, IL-6, and IFN-γ as diagnostic biomarkers for preeclampsia. The findings support their use in clinical practice to improve diagnosis, treatment, and patient outcomes, providing new insights into the pathophysiology of preeclampsia with regards to endothelial dysfunction, inflammation and immune dysregulation and may inform the development of novel therapeutic strategies for preeclampsia, providing avenues for the prevention and treatment of the condition.