Abstract Background Gestational diabetes (GDM) is defined as carbohydrate intolerance that begins or is first recognized during pregnancy. Gestational diabetes mellitus (GDM) affects approximately 5 to 7% of pregnancies and is associated with increased risk for fetal overgrowth, cesarean delivery, birth trauma, and pre-eclampsia. Objective To investigate serum FGF21 concentrations in a sample of Egyptian patients with GDM as compared with healthy pregnant controls matched for gestational age And its correlation to clinical and biochemical changes (Glucose, insulin, lipids) and fetal wellbeing using obstetric ultrasound to assess fetal size and development of congenital malformation. Methods This cross-sectional study was conducted on 80 participants collected from Obstetrics and Gynecology clinic at Ain Shams University Hospital during the period from November 2019 to March 2021. Results Shows that there is statistically significant increase in FGF21 in female pregnants with GDM as compared to female pregnants without GDM. The high FGF21 level didn’t affect fetal wellbeing. And both groups had normal fetal development with absence of macrosomia and congenital malformation as shown on results of obstetric ultrasound. In addition, there is statistically significant positive correlation between fasting FGF21 level and each of total cholesterol, LDL, HDL and TG (R +ve, P.< 0.05). Conclusion This high level of FGF21 may be FGF21 resistance or compensatory response to the underlying metabolic stress. FGF21 may have reduced an even higher level of blood glucose than the measured one, blood glucose level could have been in the Range of 400-500 mg/dl instead the measured range 200-300 mg/dl. Obstetric ultrasound results revealed normal fetal wellbeing and no change in fetal size nor development of congenital malformation between both groups.