Background: Betle leaf (BL) is an ancient herb with a potential nontoxic natural antioxidant efficacy. Oral intake and chewing betel leaves have an effort on the moving parts of salivary gland and induce salivation and detoxification; hence plays a vital role in oral hygiene. BL produces and activates various salivary enzymes which include α-amylase, lipase, lysozyme, and lactoperoxidase. BL possess antibacterial, antioxidant, anti-diabetic, immunomodulatory, and antihypertensive properties. Hence, it can be effective in the treatment of hypertensive disorder of pregnancy like preeclampsia (PE). Objective: In this context, two extracts of BL (Salivary BL extract [SBLE] and diastase BL extract [DBLE]), proved to impart efficient radical scavenging activity in our previous research work were utilized to analyze their efficacy on the level of 4-hydroxy nonenal (4-HNE), heme oxygenase-1 (HO-1), asymmetric dimethylarginine (ADMA), adiponectin/leptin in the trophoblast isolated from placental tissue of both normotensive and preeclamptic patients. Materials and Methods: Trophoblasts were isolated from both subjects and incubated with different extracts of Piper betle (saliva and diastase) to assess the cellular stress in placental trophoblast during PE. Results: Results demonstrate that extracts of BL exhibit a significant role in regulating 4-HNE, ADMA, leptin, HO-1, and adiponectin in preeclamptic trophoblasts. Still, SBLE showed relatively higher efficiency in defining the level of 4-HNE, ADMA, leptin, HO-1, and adiponectin in preeclamptic trophoblasts than DBLE, suggesting that it may be attributed to the interaction of the phytochemicals present in BL with the components of saliva. Conclusion: Hence, BL may be recommended as the effective natural remedy in the management of pathological complications of PE; which may preclude low birthweight babies and ensure live fetal delivery. Abbreviations Used: 4-HNE: 4-hydroxy-nonenal, ADMA: Asymmetric dimethylarginine, BL: Betel leaf, BLE: Betel leaf extract, CO: Carbon monoxide, DB: Diastase with betel leaf, DBLE: Diastase betel leaf extract, ELISA: Enzyme-linked immunosorbent assay, eNOS: Endothelial nitric oxide synthase, FBS: Fetal bovine serum, GSH: Reduced glutathione, HBSS: Hank's balanced salt solution, HO-1: Heme oxygenase-1, iNOS: Inducible nitric oxide synthase, NO: Nitric oxide, NOS: Nitric oxide synthase, PE: Preeclampsia, ROS: Reactive oxygen species, SB: Saliva with betel leaf, SBLE: Salivary betel leaf extract.