Background: Corona virus Disease, 2019 has been pandemic all over the world due to its strong human to human transmission. A number of measures have been put in place to prevent its spread among the population. However, for these preventive measures to be effective, the population should practice an appropriate COVID-19 prevention method. To our knowledge, there is no study yet done in the Amhara region. Thus, this study was aimed at assessing mask wearing practice and its associated factors for COVID-19 prevention among residents of metropolitan towns in the Amhara region, Ethiopia. Methods: A community-based cross-sectional study was conducted from June 20 to July 10, 2020. A total of 413 residents of metropolitan towns of the Amhara region, Ethiopia were enrolled in the study. A systematic sampling technique was used to collect data from selected households. Data were entered into EPI-DATA version 3.1 and then exported to SPSS version 24.0 for analysis. To identify the factors of mask wearing practice for COVID-19 prevention, multiple binary logistic regression analysis was used. Statistical significance was declared at p-value<0.05. An adjusted odds ratio with 95% confidence intervals was used to assess the direction and strength of associations. Results: Four hundred thirteen residents were participated in the study with a response rate of 97.6%. Of these, 234 (56.6%) were female, 229 (55.4%) were lay in the age group of 31–45 years old, and 321 (77.7%) were married. The proportion of residents who had good mask wearing practice in the current study was 57.1% [(95%CI: 52.35%, 61.94%)]. Having formal education [AOR = 5.046, 95% CI (2.713, 9.385], employed [AOR = 1.827, 95% CI (1.172, 2.848)], having good knowledge [AOR = 3.125, 95% CI (1.361, 7.178)], and having positive attitude [AOR = 2.279, 95% CI (1.09, 4.767)] were significantly associated with mask wearing practice. Conclusion: more than half of the study respondents had good mask wearing practice regarding COVID-19 prevention. Having formal education, being employed, having good knowledge, and having positive attitude were significantly associated with mask wearing practice. It is recommended that local health authorities should implement interventions such, residents training and awareness creation activities to enhance residents to develop mask wearing practice.