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Introduction: Work-related musculoskeletal disorders have a greater negative impact on nurses' well-being, both physically and emotionally. Because of this issue, nurses take excessive leave, are absent from work, quit their profession, and have a lower quality of life. This leads to an increase in human and economic losses to health care institutions. However, there is a paucity of information about work-related musculoskeletal disorders among nurses in the study area. Objective: This study aimed to assess the magnitude of work-related musculoskeletal disorders and its factors associated among nurses in Hospitals of West Shoa Zone, Central Ethiopia, 2021. Materials and methods: A cross-sectional facility-based study was conducted with 406 systematically selected nurses from March 2021 to June 2021. A simple random sampling was used to select study subjects. Data were gathered through face-to-face interviews. The data has been cleaned and checked, entered Epi Data 3.1, and exported into Statistical Package for Social Sciences software version 25 for further analysis. Bivariable and multiple logistic regressions were used to determine the factors associated with outcome variable. The level of statistical significance was reported to be less than 0.05. Results: The prevalence of work-related musculoskeletal disorders was 73.8% and the highest report 247 (62.2%) was seen in the lower back which was followed by the neck 182 (45.8%) and elbow 126 (31.7%), while the lowest affected body part was ankle 46(11.6%). Working in the medical ward (COR = 5.91, 95%CI: 2.53–13.79), surgical ward (COR = 9.63, 95%CI: 3.64–15.51), and operation room theater (COR = 6.02, 95%CI: 2.37–15.27) had higher risk to work-related musculoskeletal discomfort as compared to those who were worked in outpatient department. Nurses those experienced bending or twisting back as a problem during work 2.33 times more likely to have higher risk WMSDs as compared to those who didn't perceive it with (COR 2.33, 95% CI: 1.47–3.71). Conclusion: In this study, the prevalence of work-related musculoskeletal disorders among nurses was high. Working in room/ward, working in malposition, have no on job training to prevent work-related musculoskeletal disorders and bending or twisting back during work were identified as associated factors. Since work-related musculoskeletal disorders are preventable, educating the staff about the use of proper body mechanics and modifying the work environment is essential. [ABSTRACT FROM AUTHOR]