Introduction: Pain is an unpleasant sensory and emotional experience associated with actual or potential damage. Recently, in developing countries including Ethiopia, there is insufficient data regarding the knowledge and practice of neonatal pain management among nurses. Hence, the current study identified the nurses’ knowledge, practice, and factors associated with neonatal pain management at west Oromia public hospitals. Objective This study aimed to assess knowledge, practice, and factors associated with neonatal pain management among nurses at west Oromia public hospitals, Ethiopia 2022. Methods An Institutional-based cross-sectional study design was used to conduct the study from all thirty-five public hospitals in west Oromia, from May 1 to 30/2022. A simple random sampling technique was used to select the study participant. The data was entered into Epi-data version 4.6 and exported to SPSS version 26 for analysis. Descriptive statistic was presented in text, tables, and charts. Bivariable and multivariable logistic regression was computed considering the p-value < 0.05 to identify statistically significant factors. Result This study was conducted with 203 staff nurses’ working in the neonatal intensive care unit with a response rate of 98.5%. 127(62.6%) of the nurses had adequate knowledge regarding neonatal pain management. As a practice, 33(16.3%) of the participant had a good practice. There was a significant association between nurses’ knowledge status and getting training on neonatal pain management at university/college (AOR, 2.31; CI 1.29, 4.27). The knowledge level (AOR, 3.3 CI: 1.14, 9.32), having a pain management policy in place (AOR, 5.44, CI: 1.92, 15.37), and receiving training on neonatal pain management at university/college (AOR, 2.55 CI: 1.09, 5.97) were significantly associated with the practice of nurses. Conclusion and Recommendation: The finding revealed that nurses had inadequate knowledge and practice in neonatal pain management. Though the level of nurses’ knowledge of neonatal pain management is mediocre and the level of nurses’ practice in neonatal pain management is unpredictably low. Therefore, providing training on neonatal pain management at university/college, providing on-job training, and endorsing pain management policy have a paramount role in improving nurses’ knowledge and practice on neonatal pain management.