This study describes postpartum depression rates and risk factors for mothers with infants with cleft lip and/or palate as postpartum depression has been associated with a range of negative maternal and child outcomes. A retrospective chart review from August 2009 to May 2015 included medical diagnoses, demographics, receipt of prenatal diagnosis, and the Edinburgh Postnatal Depression Scale (EPDS). Mothers (N = 206) had infants (59.2% male; mean age in weeks 5.1 ± 6.9) with isolated cleft lip (18%), cleft palate (22.8%), or cleft lip and palate (59.2%). Mothers ranged from 16 to 45 years old (mean age 29 ± 6.2) and half had received a prenatal diagnosis. Patients mostly had public insurance (57.8%) and represented diverse ethnicities. Based on the EPDS, 11.7% of mothers met the depression cutoff of 10 or higher. The majority endorsed self-blame (68.9%), difficulty coping (59.2%), and feeling anxious (57.3%). Mothers of infants with cleft lip or cleft lip and palate who did not receive a prenatal diagnosis had higher total EPDS scores, anxiety, and incidence of feeling scared. Higher EPDS scores were predicted by not having a prenatal diagnosis and by older maternal age. Mothers of infants with a cleft had similar rates of postpartum depression as the general population; however, those who were older and who did not receive a prenatal diagnosis endorsed more symptoms. Prenatal diagnosis may contribute to positive maternal postpartum adjustment. Providers should incorporate screening for risk factors into their evaluation and treatment planning.