Background: Disrupted maternal prenatal cortisol production influences offspring development. Factors influencing the hypothalamic-pituitary-adrenal axis include social (e.g., stressful life events) and physical/chemical (e.g., toxic metals) pollutants. Mercury (Hg) is a common contaminant of fish and exposure is widespread in the US. No prior study has examined the joint associations of stress and mercury with maternal cortisol profiles in pregnancy. Objectives: To investigate potential synergistic influences of prenatal stress and Hg exposures on diurnal cortisol in pregnant women. Methods: Analyses included 732 women (aged 27.4 ± 5.6 years) from a Mexico City pregnancy cohort. Participants collected saliva samples on two consecutive days (mean 19.52 ± 3.00 weeks gestation) and reported life stressors over the past 6 months. Hg was assessed in toe nail clippings collected during pregnancy. Results: There were no main effects of Hg or psychosocial stress exposure on diurnal cortisol (ps > .20) but strong evidence of interaction effects on cortisol slope (interaction B = .006, SE = .003, p = .034) and cortisol at times 1 and 2 (interaction B = -.071, SE = .028, p = .013; B = -.078, SE = .032, p  = .014). Women above the median for Hg and psychosocial stress exposure experienced a blunted morning cortisol response compared to women exposed to higher stress but lower Hg levels. Conclusions: Social and physical environmental factors interact to alter aspects of maternal diurnal cortisol during pregnancy. Research focusing solely on either domain may miss synergistic influences with potentially important consequences to the offspring.