This study investigates the sex-specific programming of offspring emotionality after prenatal stress. Male offspring exposed to stress early in gestation displayed maladaptive behavioral stress responsivity, anhedonia, and increased sensitivity to selective serotonin reuptake inhibitor (SSRI) treatment. Long-term alterations in central corticotropin-releasing factor (CRF) and glucocorticoid receptor (GR) expression, as well as increased hypothalamic–pituitary–adrenal (HPA) axis responsivity, were observed in these mice, contributing to elevated stress sensitivity. Changes in CRF and GR gene methylation correlated with altered gene expression, indicating epigenetic programming during early prenatal stress. Additionally, sex-specific placental responsivity was found, with stress early in pregnancy significantly increasing the expression of PPARα, IGFBP-1, HIF3α, and GLUT4 in male placentas but not females. These findings suggest that early prenatal stress may contribute to male neurodevelopmental disorders through impacts on placental function and fetal development.This study investigates the sex-specific programming of offspring emotionality after prenatal stress. Male offspring exposed to stress early in gestation displayed maladaptive behavioral stress responsivity, anhedonia, and increased sensitivity to selective serotonin reuptake inhibitor (SSRI) treatment. Long-term alterations in central corticotropin-releasing factor (CRF) and glucocorticoid receptor (GR) expression, as well as increased hypothalamic–pituitary–adrenal (HPA) axis responsivity, were observed in these mice, contributing to elevated stress sensitivity. Changes in CRF and GR gene methylation correlated with altered gene expression, indicating epigenetic programming during early prenatal stress. Additionally, sex-specific placental responsivity was found, with stress early in pregnancy significantly increasing the expression of PPARα, IGFBP-1, HIF3α, and GLUT4 in male placentas but not females. These findings suggest that early prenatal stress may contribute to male neurodevelopmental disorders through impacts on placental function and fetal development.