Background: Pain is the most common challenge that most hospitalized patients complain of during their hospital stay. It is influenced by several patients, nurses, and institutional-related factors. Most prior studies in Ethiopia on pain are focused on surgical illnesses. Objective: To assess nurses' pain management practice and associated factors for admitted patients at Comprehensive Specialized Hospital of the Amhara Regional State, Ethiopia, 2022. Methods and materials: A multi-center institution-based cross-sectional study was conducted at the Comprehensive Specialized Hospitals of the Amhara region. A total of 430 nurses and patients for whom the nurses responsible were included in the study. Data were collected from nurses, patients, and charts of patients using self-administered, structured, and checklist questions respectively. The overall practice was categorized as good, moderate, and poor using the modified bloom’s criteria. An ordinal logistic regression model was applied, and variables with a p-value of ≤ 0.25 in the bivariable analysis were taken to multivariable analysis. Variables with a p-value < 0.05 with a 95% CI were considered significant. The results were presented in text, tables, and graphs. Results: The study evaluated the pain management practices of 430 nurses. Of those, 25.8%, 27.5%, and 46.7% had good, moderate, and poor pain management practices respectively. The odds of being in a higher level of pain management practice was higher for nurses with degrees and above (AOR=2.282: 95%CI [1.181, 4.41]), who attended in-service training (AOR=2.465: 95%CI [1.317, 4.614]), providing care for patients with painful procedures (AOR=5.648: 95%CI [3.237, 9.856]) and severe pain (AOR=2.573: 95%CI [1.35, 4.899]), and working in the institutions having a pain-free initiative focal person (AOR=6.339: 95%CI [3.611, 11.13]. Conclusion and recommendation: Overall, the majority of nurses had poor pain management practices. Five variables from nurses, patients, and institution were found to have a statistically significant association with nurses' pain management practices. Patients would be benefited considerably if hospitals focus on providing training and assigning focal persons for advocating regular management for patients at any pain level. Keywords: pain, hospitalized patients, nurses, pain management practice, Amhara region