Introduction Nurses in perinatal care are the initial point of interaction making them crucial for early detection of depression among pregnant or birthed women. Though prevalent, there is limited data on the knowledge levels, attitudes, and practice among nurses in Ghana toward perinatal depression. This study investigated nurse’s knowledge, attitude, and practices on perinatal depression at two hospitals in Ghana. Methodology 211 perinatal care nurses at the Korle Bu Teaching Hospital and the Greater Accra Regional Hospital were surveyed on their knowledge, attitude & practices on perinatal depression and analyzed using STATA version 15. Logistic regression was performed to determine factors associated with nurses’ and midwives’ practices toward the identification and management of perinatal depression. At a confidence interval of 95%, a p value of <.05 was considered statistically significant. Results Nearly half of the nurses (47.4%) of nurses depicted inadequate knowledge, 46.9% had an overall poor attitude toward identification and management of perinatal depression, and 79.6% depicted poor practices toward the identification and management of perinatal depression. Conclusions This study highlights knowledge gaps and suboptimal attitudes and practices regarding perinatal depression among nurses in Ghana. Addressing these gaps through targeted education and training may enhance early identification and management of perinatal depression in perinatal care settings.