Introduction Coronavirus 2019 (COVID– 19) is an acute respiratory viral infectious disease in human being caused by RNA virus that belonged to the family of corona virus. The incidence of this disease was growing exponentially and affects millions of the world population that leads to expose thousands of peoples for death. Thus, this study was targeted to assess the practice of people on COVID-19 infections prevention strategies in the region. Methods A community based cross sectional study design was conducted in Benishangul Gumuz Region from May 25 –June 15, 2020. Multistage sampling technique was carried out to select 21 kebeles/ketena and 422 study participants. Data were collected by face to face interview using semi-structured questionnaires. The collected data were entered, cleaned and analyzed using STATA software version 14.0. Descriptive, bi-variable and multivariable multilevel models were applied. Variables with p value < 0.25 in bi-variable analysis were selected as candidates for multivariable analysis. Finally, the variables with p-value < 0.5 were considered as statistically significant, then variables with odds ratio, 95% CI were used to interpret the effect of association. Results The magnitude of good practice on prevention strategies of COVID– 19 infections was 62.1%. The most frequently practiced prevention strategies for COVID-19 infections were hand washing with water and soap (80.7%), alcohol-based hand rub (68.8%), maintaining social/physical distance (74.2%) and avoiding touching eyes. Individual and community level factors that affecting practice of COVID– 19 infection prevention strategies were discovered. Hence, community level factor was place of origin (AOR = 0.1; 95%CI: 0.03, 0.35) whereas individual level factors were able to read and write (AOR = 0.18; 95%CI: 0.04, 0.81) and being merchant (AOR = 2.07; 95%CI: 1.01, 4.28). Conclusion The level of practice of community towards COVID-19 infections prevention strategies were low as compared with the expected outcome. Individual and community level factors were identified. This implies that social mobilization and community engagement was not effective. Thus, designing appropriate strategies to improve of practice prevention strategies are strongly recommend.