Objective Despite improved patient outcomes, health service quality, patient safety and clinical effectiveness are among its successes, evidence-based utilisation among health professionals in Ethiopia was found to be low. Implementing the evidence-based practice (EBP) system in Ethiopia is hampered due to organisational and cultural barriers such as lack of internet, lack of computer access, absence of digital libraries to search for up-to-date information. Therefore, this study aimed to assess EBP and associated factors among health professionals working at public hospitals in South Wollo zone, Amhara region, Ethiopia, 2023. Setting, participants and outcome measures An institution-based cross-sectional quantitative study supplemented with qualitative design was conducted from December 1 to January 10, 2023. A total of 422 health professionals were included using single population proportional allocation. Quantitative data were collected using self-administered questionnaires. Descriptive statistics, bivariable and multivariable logistic regression analyses with adjusted odds ratio (AOR) (95% CI) were performed at p value <0.05. Variables with p value <0.2 in the bivariable analysis were selected for multivariable logistic regression, and variables with p value <0.05 in the multivariable logistic regression were taken as significant factors. The results were displayed using tables and graphs. For the qualitative study, an in-depth interview with open-ended questions was prepared, and the collected data were analysed using the thematic analysis method with OpenCode software V.4.02. Results A 94.8% response rate was achieved and the mean age of the participants was 32.07 +/- SD= 6.2. 47.3% of the health professionals had good EBP. Health professionals who were married (AOR = 1.75 (95% CI 1.02 to 2.98), age category 20-29 years (AOR =1.34 (95% CI 1.20 to 3.01)), had favourable attitude (AOR =1.70 (95% CI 1.09 to 2.64)), worked >= 8 hours (AOR =1.96 (95% CI 1.20 to 3.19)), had good knowledge (AOR =1.34 (95% CI 1.13 to 2.18)) and trained on EBP (AOR =5.52 (95% CI:2.99 to 10.19)) were contributing factors. Conclusion We observed that EBP was utilized insufficiently. Marital status, attitude towards evidence-based practice, working >=8 hours, knowledge and training on evidence-based practice were statistically significant. Enhancing a positive attitude to use evidence-based practice in clinical decision-making, boosting knowledge, allocating more time to search for information and providing evidence-based practice training are mandatory to improve evidence-based practice.