Background Medical care facilities in both developed and developing countries around the world continue to invest in hospital information technologies (HITs). Nevertheless, it has been discovered that user acceptance of these technologies is one of the imperative issues during their implementation and management in developing countries such as Ghana. Purpose Notably, the technology acceptance assessment of nurses is a timely one since they play a very important role in the medical sector. Based on the model of “Unified Theory of Acceptance and Use of Technology,” this study explored the factors that affect Ghanaian nurses’ acceptance of HIT. Design/Method/Approach: A descriptive nonexperimental research design was employed in this study to recruit 660 nurses (404 females and 256 males) from 3 teaching and 2 regional hospitals in Ghana. A standardized electronic platform questionnaire (based on the Unified Theory of Acceptance and Use of Technology model) was designed on smartphones and was self-administered, while the data collected were analyzed via the SmartPLS Structural Equation Modeling path analysis. The “Social Influence” ( t = 3.656, p < .001), “Attitude towards the Use of Technology” ( t = 5.861, p < .001), and “Facilitating Conditions” ( t = 2.616, p < .001) were the main predictors of the nurses’ behavioral intention to use HIT. The effects of the aforementioned constructs explained 60.7% ( R2 = 0.607) of the variance in the nurses’ intentions to use the HIT systems. Conclusions Precisely, HIT systems are essential in the quality and the enhancement of nursing services provision and in the effectiveness of the performance of nursing staff. This study, therefore, offers a piece of empirical evidence for hospital administrators in developing countries especially Ghana, to assess the success probability of new HITs before and after their implementation.