Background: Picture archiving and communication system is an innovation system in the health information that reduces costs, facilitates access to medical image, and improves workflow in radiology department. However, studies indicated that intention and usage of picture archiving and communication system is limited in middle-income and developing countries. Objective: This study aimed to assess the intention to use picture archiving and communication system and its predictors among physicians and nurses at specialized teaching hospitals in Amhara region, Northwest Ethiopia. Method: Institution-based cross-sectional study design was conducted from October 11 to November 12, 2023. Proportional allocation and a simple random sampling were used to select participants of the study. A self-administered structured English questionnaire was used, and a 5% pretest was performed. Data were entered into Epi data 4.6 and exported to SPSS 26 and AMOS 23. Descriptive and structural equation modeling analysis was performed. The hypothesis was tested using a path coefficient and a p-value <0.05. Results: About 54.7% (95%: CI: 50.9–58.4) of the participant intended to use picture archive and communication system with a 90.38% of response rate. Performance expectancy (β = 0.146, p-value <0.05), perceived enjoyment (β = 0.397, p-value <0.001), and computer literacy (β = 0.191, p-value <0.001) had positive influence on intention to use picture archiving and communication system. Conclusions: Overall, more than half of physicians’ and nurses’ intention to use picture archiving and communication system were at hopeful stage for future. Performance expectancy, perceived enjoyment and computer literacy had direct positive effect on intention to use picture archiving and communication system among physicians and nurses. The designers, developers, and managers of the picture archiving and communication system should consider these variables. Furthermore, using this system can improve quality of health service through change workflow in to digital image, clinicians evaluate image more quickly and saving resources.