Aims: Using ergonomics principles are effective on increasing production, job satisfaction productivity, and reducing medical and healing costs. This study investigated the relationship between nurses' knowledge of ergonomic principles with their musculoskeletal disorders (MSDs). Materials and Methods: This descriptive and analytical study was performed on 260 nurses working in selected hospital in Kashan/Iran, 2018. The nurses were randomly recruited to the study. Data were collected through personal profile questionnaires, knowledge of the ergonomics of the workplace, the questionnaire of the workplace ergonomics, and Nordic skeletal musculoskeletal questionnaire. Data were analyzed using the SPSS version 16 software. Descriptive statistics (frequency distribution, mean, and standard deviation) and inferential statistics (Chi-square, Fisher's exact, and Pearson's correlation coefficient) were used for data analysis. Results: The nursing staff had low level of knowledge with a mean score of (2.20 ± 0.68). The ergonomic condition of the nurses' work environment was weak (2.50 ± 0.76). About 77% of participants reported the MSD (neck 62.7% and shoulder pain 49.2%) and the least difficulty was in the elbow region (20.4%). There was a significant and negative correlation between knowledge of ergonomics principles (r = −0.180) and ergonomics condition of the workplace (r = −0.160) with musculoskeletal injuries. Conclusion: The study findings indicated low level of knowledge of the nurses regarding the ergonomics of workplace principles. Furthermore, results showed the ergonomics of the workplace was poor. The prevalence of MSD was high, which needs appropriate training and respecting ergonomics principles in the workplace.