Perinatal depression is the most prevalent mental health complication during pregnancy, with significant consequences for both mother and child. Despite advances in obstetric care, the emotional well-being of mothers remains under-addressed. Ketamine and esketamine have garnered attention due to their rapid antidepressant effects, particularly when traditional treatments may not provide immediate relief. Perioperative low-dose ketamine can reduce depressive symptoms and prevent the onset of postpartum depression in Cesarean section. Esketamine offers enhanced antidepressant effects and a quicker recovery profile with fewer side effects. Nevertheless, use of both ketamines in the perinatal period raises important safety concerns. Our review will address potential adverse neurodevelopmental effects on the fetus and the risks for breastfed neonates which are not well understood. Short-term side effects, such as dissociative symptoms and transient cardiovascular effects in the mother must be monitored and, if necessary, managed. More research is needed to better understand the effects of ketamine in peripartum depression, particularly in lactating mothers, for the safety of mothers and infants.