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Introduction: Pain management is a very important aspect of nursing care. However, due to a lack of overall understanding, it is not uncommon to see inadequate pain management by health workers. Therefore, the knowledge and attitude of nurses are important factors for the effective management of pain in children. Thus, the objectives were to determine the knowledge and attitude toward pediatric pain management among the nurses in the University of Gondar Comprehensive Specialized Hospital, Northwest Ethiopia. Methods: An institutional-based cross-sectional study was conducted from 1 to 30 March 2020 among 393 participants. A simple random sampling technique was used to select the study subjects. The data were collected by using a structured, pre-tested, self-administered questionnaire. The data were entered into EpiData version 3.02 and exported into SPSS version 22 for analysis. Bivariable and multivariable logistic regressions were computed to identify the factors associated with the knowledge and attitude of nurses. An adjusted odds ratio with a 95% confidence interval was computed, and variables with a p -value 10 years of work experience (AOR = 9.02; 95% CI = 2.50–32.74) were significantly associated with the attitude toward pediatric pain management. Conclusion: The majority of nurses had good knowledge and a favorable attitude toward pediatric pain. Working in the outpatient department was associated with poor knowledge. Trained nurses, having good knowledge, and having >6 years of work experience were associated with favorable attitudes.