Introduction Non-pharmacological pain management practices are very important for the successful treatment of pain. It has an impact on the patient’s quality of life and the family’s financial situation owing to missed workdays, direct medical expenses, and incapacity from pain. Objective Therefore, this study is intended to assess non-pharmacological pain management practice and associated factors among nurses working at comprehensive specialized hospitals in northwest, Ethiopia. Methods Institution-based cross-sectional study design was employed from May 30 to June 30, 2022. A stratified random sampling technique was used to select 322 study participants. A binary logistic regression model was used to identify factors associated with non-pharmacological pain management practice. Variables with a P-value less than .25 in the bi-variable analysis were entered into the multivariable logistic regression analysis and a P-value of less than .05 was considered as having a statistically significant association. Results A total of 322 nurses participated, with a response rate of 98.8%. It was found that 48.1% (95% CI: 42.65, 53.62) of nurses had good practice in non-pharmacological pain management. Pain assessment tool availability (AOR = 1.68 [95% CI: 1.02, 2.75]) ( P = .04), good pain assessment practice (AOR = 1.74 [95% CI: 1.03, 2.84]) ( P = .03), favorable attitude (AOR = 1.71 [95% CI: 1.03, 2.95]) ( P = .03), and age (26–35) (AOR = 4.46 [95% CI: 1.24, 16.18]) ( P = .02) were factors significantly related to non-pharmacological pain management practice. Conclusion According to this work, the prevalence of non-pharmacological pain management practices was found to be low. Good pain assessment practices, availability of pain assessment tools, favorable attitude, and age (26–35) years were significant factors of non-pharmacological pain management practice. Hospitals are better give training on non-pharmacological pain management methods for nurses as they are important to treat pain holistically, increase patient satisfaction, and are cost-effective.