Staff shortages, deficient knowledge, inappropriate attitudes, demanding workloads, analgesic shortages, and low prioritization of pain management have been identified in earlier studies as the nursing-related barriers to optimal children’s pain management. These studies have mainly been undertaken in developed countries, which have different healthcare dynamics than those in developing countries. The current study, therefore, sought to identify and understand the nursing-related barriers to children’s pain management in the Ghanaian context. A descriptive qualitative study was conducted among 28 purposively sampled nurses working in the pediatric units of five hospitals in the Ashanti region of Ghana. Over the course of three months, participants were interviewed on the barriers which prevented them from optimally managing children’s pain in practice. Recorded interviews were transcribed verbatim and deductively analysed based on a conceptual interest in pain assessment and management-related barriers. NVivo 12 plus software guided data management and analyses. The mean age of participating nurses was 30 years, with majority being females (n = 24). Participants had worked in the nursing profession for an average of five years and in the pediatric care settings for an average of two years. The nursing-related barriers identified in the present study included communication difficulties in assessing and evaluating pain management interventions with children who have nonfunctional speech, insufficient training, misconceptions on the experience of pain in children, lack of assessment tools, and insufficient number of nurses to manage the workload and nurses’ inability to prescribe analgesics. The present study revealed some barriers which prevented Ghanaian nurses from optimally managing children’s pain. Nurses should be educated, empowered, and supported with the requisite material resources to effectively manage children’s pain and improve outcomes for families, healthcare systems, and the nation. Future studies should explore the facilitators and barriers from other stakeholders involved in pediatric pain management.