Background: Pain management is one part of management in the postoperative period. The prevalence of moderate to severe postoperative pain and its functional interference is high in Ethiopian patients. In this study we aimed (1) to assess nurses' knowledge and attitudes regarding post-operative pain management; (2) to identify the factors of nurses' knowledge and attitudes. Method: A cross-sectional multicenter study was conducted. All nurses working in Amhara region referral hospitals were involved in the study. The Nurses' Knowledge and Attitudes Survey Regarding Pain (NKASRP) was used to measure the nurses' pain management knowledge and attitudes. Bivariable and multivariable logistic regression was used to identify factors associated with knowledge and attitude. Results: A total of 433 nurses were included. Of the total respondents, 90.6% of them had a bachelor's degree with work experience of between 1 to 5 years (58.5%). Only 76 (19.2%) participants got access to read journals and 66 (16.7%) had taken training regarding postoperative pain management. The results showed that 56.5% [95% CI= (51.6-61.3)] respondents had adequate knowledge and 8.9% [95% CI= (6.1-11.6)] of them had positive attitudes towards POP management. Higher level of education [AOR=8.2; CI= (2.51-26.83)], getting access to read journals [AOR =1.83; CI= (1.01-3.30)], and taking POP management training [AOR=8.63; CI= (3.67-20.28)] were statistically associated with adequate knowledge. Similarly, positive attitude towards postoperative pain management was associated with taking POP management training, available of pain management course in the curriculum, and getting access to read. Conclusion: Although more than half of nurses in the study area had adequate knowledge towards POP management, only a small number had a positive attitude. Taking POP management training and getting access to read journals were significantly associated with good knowledge and attitude towards POP management; therefore, regular in-service training and getting accessing reading materials (such as journals or articles) are recommended to enhance quality service to patients.