Postpartum depression is a relatively common occurrence that may carry lifelong consequences. Also common is the exposure of pregnant and postpartum women in the United States to antibiotics, especially during the peripartum period. Antibiotic exposure is known to alter gut microbial composition and structure, contributing to a dysbiotic, or imbalanced gut microbiome, and is a mechanism suggested for the increased risk of depressive symptoms following antibiotic exposure in non‐pregnant, non‐postpartum populations. We sought to determine the relationship between antibiotic exposure intrapartum through the first 14 days postpartum and depressive symptoms within the first 6‐months postpartum. In this secondary data analysis, 124 pregnant women from a prospective cohort were enrolled into the study and provided demographic characteristics and health history. Participants completed questionnaires including the Edinburgh Postnatal Depression Scale between 32–36 weeks, and 1‐ and 2‐weeks and 1‐, 2‐, 3‐, and 6‐months postpartum. Clinical measures including hours in labor, perineal injury, and mode of giving birth were ascertained by medical record abstraction. Antibiotic exposure was identified by self‐report at 1‐ and 2‐weeks postpartum. Antibiotic exposure was found to be independently predictive of postpartum depressive symptoms at 1‐month (Beta = 0.43; CI [0.01, 0.86]) and 2‐months (Beta = 0.51; CI [0.08, 0.94]) postpartum after controlling for baseline predictors. The relationship between antibiotic exposure and postpartum depressive symptoms did not maintain significance at 3‐ or 6‐months postpartum. Additional studies are needed to further investigate the relationship between onset and duration of antibiotic exposure, the peripartum gut microbiome, and the risk for postpartum depressive symptoms.