Background: Poorly managed postoperative pain is linked to numerous postoperative complications worldwide and in Ghana. This is due to the myriad of physical and psychological problems, such as lifelong chronic pain syndromes, impaired functionality and death. Purpose: The aim of this study was to assess the barriers and factors influencing postoperative pain management by Ghanaian nurses working in four hospitals. Methods: A quantitative descriptive cross-sectional design was employed for this study. Participants were recruited using a multistage sampling technique by which 146 returned their questionnaires out of 194 participants. The statistical analysis of data was done with the Statistical Package of Social Sciences (SPSS) 20.0 version. Results: Findings revealed that some verbal and non-verbal cues from patients such as facial grimacing, restlessness, irritability and distress, lack of concentration and moaning or crying (verbalisation) influenced how nurses controlled postoperative pain with analgesia. The participants also identified several barriers to influence postoperative pain management by nurses. Conclusion: In conclusion, postoperative pain control by nurses is influenced by several factors, and hence, nurses need to manage patients’ pain effectively in Ghana and abroad using multiple approaches.