Background: The success of citizens to control the diseases is affected by their prevention practice. To the best of our knowledge, there was no study yet done in North Mecha district on prevention practice of COVID-19 on the general population. Objective: The aim of this study was to assess prevention practice towards COVID-19 and its associated factors among adults in North Mecha district. Methods: Community based cross sectional study triangulated with concurrent quantitative - qualitative study design was conducted from November 25 to December 25, 2020. A total of 631 study participants were selected using multistage sampling technique. For qualitative part, 16 study participants were selected by purposive sampling technique. Structured, interviewer- administered questionnaire for quantitative data collection and unstructured interview guide for in-depth interview of qualitative data collection were used. Descriptive statistics for data summarization, tables and graph for data presentation were used. Ordinal logistic regression analysis was employed to identify associated factors. Adjusted proportional odds ratio with 95% confidence interval was reported. P-value < 0.05 was used to declare statistically significant. Thematic analysis was employed for qualitative data analysis. Results: A total of 624 study participants were participated with a response rate of 98.9%. About 3.53%, 95% CI (2.1– 5.0%), 7.53%, 95% CI (5.6–9.7%) and 88.94%, 95% CI (86.5– 91.4%) of adults had good, moderate and poor prevention practice respectively. Age of 41-50 years verses age greater than 50 years (AOR=3.83, 95% CI, (1.18-12.40)), age of 31-40 years verses age greater than 50 years (AOR= 3.69, 95% CI, (1.12-12.24)), urban verses rural residence (AOR= 5.40, 95% CI, (2.58-11.27)),good verses poor knowledge (AOR= 3.49, 95% CI, (1.71-7.13)), positive verses negative attitude (AOR= 8.16, 95% CI, (4.37-15.23)) and poor verses good accessibility of sanitizer(AOR= 0.16, 95% CI, (0.06-0.45)) were significantly associated factors. Fear of criticism, ignorance and negligence were explored as barriers. Conclusion: prevention practice of adults was poor. Age, residence, knowledge, attitude and accessibility of sanitizer were associated factors. Fear of criticism, ignorance and negligence were barriers for prevention practice. Health education to all adults, due attention in all aspects of prevention practice to older peoples and rural adults and ensuring accessibility of sanitizer is needed. Keywords: COVID-19, prevention practice, Ethiopia.