BACKGROUND: Pressure injury is a preventable public health problem. It may develop due to intense force or force combined with shear. Pressure injuries may be associated with pain and increased length of hospital stay. Adequate knowledge and a positive attitude of nurses are required to prevent pressure injuries. Evidence on pressure injury prevention in Ghana among nurses is limited. AIMS AND OBJECTIVES: The study examined factors associated with nurses' knowledge and perceived barriers toward pressure injury prevention in the Tamale metropolis, Ghana. METHODS: This was a multi-center descriptive cross-sectional study that recruited 216 nurses using systematic random sampling method. Data were collected using a self-administered questionnaire and analyzed using the R package and Statistical Package for Social Scientists (SPSS) version 27.0. After controlling for covariates, regression analysis determined the predictors of knowledge and attitude toward pressure injury prevention. RESULTS: More than two-thirds (79%) of nurses demonstrated good knowledge regarding pressure injury prevention. However, a significant majority (94%) exhibited poor attitudes. Notably, nurses employed in teaching hospitals [aRR = 2.09 (95%CI: 1.31, 3.44), CONCLUSION: While nurses exhibited a good knowledge about pressure injury prevention, their attitude toward its prevention was poor, indicating significant gaps that need addressing. Developing a comprehensive pressure injury management document and promoting attitudinal change through continuing professional capacity development may prove timely. The findings highlight the need for addressing organizational barriers that hinder effective nursing practice to improve the quality of care and positive patient outcomes.