Background: Globally, COVID-19 remains public health problems with high morbidity and immature death. However, preventive practice and its determinants of prevention activities are not well studied in the study area among specific group of population. Hence, this study provides evidence towards the factors affecting the prevention and control of COVID-19. Objective: To assess the Practice of COVID-19 prevention and Associated Factors among high school students in Hawassa city, Sidama region, southern Ethiopia, 2022. Method: Institution-based cross-sectional study was conducted among a randomly selected 578 students in Hawassa city from April 1-15, 2022. Multi stage sampling technique was employed to recruit the study subjects. Data were collected by trained data collectors through a pretested structured self-administered questionnaire. The data entry and analysis were done using SPSS, v 26. Descriptive statistics and logistic regression analysis were done. Statistically significant test was declared at cutoff point of P- value < 0.05 and considering a 95% confidence interval. Result: A higher proportion of the respondents were female (56.6%) & (65.4%) from government school. The overall good practice of COVID-19 prevention measure was 136 (23.8%), at 95% CI: (20.4, 27.4) with mean and (±SD); 54.1 (±13.6). The study participants who had higher Cues to action [AOR=1.96, 95%CI: (1.23, 3.14)], high perceived susceptibility [AOR=3.05, 95%CI: (1.86, 5.01)], high perceived severity [AOR=1.60, 95%CI: (1.01, 2.54)], high information reliability [AOR=1.88, 95%CI: (1.08, 3.28)] and low perceived barrier [AOR=3.29, 95%CI: (2.11, 5.12)] were found to be associated with good practice of COVID- 19 prevention measure. Conclusion: Good practice of the prevention measures was found to be low among the study participants. High Cues to action, high perceived susceptibility, high perceived severity, better information reliability and low perceived barrier were found to be associated with good practice. Since spread of the infection among students is risk for the whole community all concerned body must work to increase compliance with preventive measures by addressing these factors.