Objective The study aimed to investigate inter-professional collaboration and associated factors among nurses and physicians working in referral and teaching hospitals in the Northwest and Ethiopia in 2022. Method This study used a concurrent (quantitative cross-sectional and phenomenological qualitative) design from September to October 2022. A structured, self-administered nurse-physician collaborative scale questionnaire was used to collect quantitative data from 279 nurses and 87 physicians. A simple random sampling technique was used to select participants. The magnitude of the association was measured using the odds ratio at a 95% confidence interval and was statistically significant at a p-value less than 0.05 using binary logistic regression analysis. Qualitative data were collected from nine key informants via focused interviews or semi-structured in-depth interviews and analyzed using ATLAS.ti version 7.0.7 software via narratives using the thematic analysis method. Result According to the study’s findings, a greater number (43.4%) of the respondents had ineffective collaboration during their professional activities. In the final model of multivariable analysis, unsatisfactory organizational support, poor professional support, and poor interpersonal support were all independently associated with ineffective collaboration. The qualitative findings identified poor communication, a lack of professionalism, and failure to adhere to professional duties as barriers to nurse-physician collaboration. Conclusion In this study, nurse-physician collaboration was less than expected; thus, the large number of participants had ineffective collaborations. Potential predictors of decreased effective nurse-physician collaboration included dissatisfaction with organizational support, poor professional support, and poor interpersonal support. This outcome emphasizes the importance of improving nurse-physician collaboration by enhancing organizational, professional, and interpersonal factors to form effective collaborative practice. The qualitative finding supports the quantitative study, which showed ineffective collaboration. The authors recommended that there is a need to empower interprofessional collaboration among nurses and physicians through the creation of a conducive and safe working environment.