Background: This study investigates the influence of maternal stress during pregnancy on maternal insulin sensitivity and Interleukin-6 (IL-6) levels in pregnant women (N = 277) in dependence of pre-pregnancy Body-Mass-Index (BMI). Methods: Gestational diabetes was diagnosed in 80 women. We used the Patient Health Questionnaire (PHQ-D) to investigate maternal stress during pregnancy with a higher scoring indicating higher maternal stress level. IL-6 and cortisol were measured and maternal insulin sensitivity was assessed with the non-esterified fatty acid insulin sensitivity index (NEFA-ISI). Generalized Linear Model analysis was used to analyze effects within different stress groups. Results: Maternal low stress symptoms during pregnancy showed no significant association with maternal insulin sensitivity or IL-6. Higher cortisol levels during pregnancy were associated with elevated IL-6 concentrations. Pre-pregnancy BMI had the strongest positive effect on IL-6 levels and was negatively associated with insulin sensitivity during pregnancy. Conclusions: Therefore, preconceptional interventions to reduce BMI are needed to improve maternal metabolism during pregnancy.