According to the International Labor Organization, occupational accidents and diseases kill millions of workers every year. To assess factors associated with the level of knowledge and self-reported practice toward safety precautions among factory workers in the East Gojjam Zone, Northwest Ethiopia, 2021. An institution-based, cross-sectional study was conducted on 420 randomly selected factory workers. Data were collected through face-to-face interviews using structured questionnaires and an observation checklist. The data were analyzed using the descriptive statistical method and using bivariate binary and multivariable logistic regression models. Variables with a p-value <0.05 with a 95% confidence interval were considered to have statistical significance. The study had a response rate of 99.0%, with a total of 416 respondents. 53.4% of respondents were aware of safety precautions, and 56.0% of them rated the use of personal protective equipment as an indicator of the practice of safety precautions. Factory workers' educational status (adjusted odds ratio: 4.3, 95% confidence interval: 2.4, 7.8), job satisfaction (adjusted odds ratio: 4.7, 95% confidence interval: 2.1, 10.4), and having training on safety issues (adjusted odds ratio: 12.8, 95% confidence interval: 6.3, 26.1) were determinant factors of knowledge regarding safety precautions, while the type of factory (adjusted odds ratio: 16.0, 95% confidence interval: 5.8, 44.1), the presence of regular supervision (adjusted odds ratio: 3.8, 95% confidence interval: 2.1, 6.8), and overall knowledge about safety precautions (adjusted odds ratio: 7.2, 95% confidence interval: 3.9, 13.2) were the independent determinants of the practice of safety precautions. Workers' knowledge and practice regarding safety precautions were low as compared to studies in developing countries. Interventions targeted at the provision of training, promotion, and enforcement of issues regarding safety precautions should be in place. Employers, the government, and employees should work together to address these workplace safety issues.