A variety of measures have been put in place in Iraq to slow the rapid spread of the COVID-19 pandemic. However, there is still little information available about students' knowledge and practice during the pandemic of COVID-19. Therefore, the purpose of this study was to evaluate knowledge, practice, and related factors, among students at secondary schools in Karbala City Iraq, toward COVID-19. A cross-sectional study was conducted from 15 December 2021 to 29 March 2022, using a self-administrated structured questionnaire among secondary students in their classes. The relationship between students' general knowledge, practice, and satisfaction with their demographic characteristics was evaluated using an unpaired t-test and a one-way ANOVA test. Total percentage of student's knowledge is (72.94%), a higher percentage (81.3%) believes that the infection can be prevented, and a lower percentage goes about the importance of the vaccine, only (50.8%) believed that the corona vaccine can decrease the severity of the infection, (63.5%) of the participants had effective preventive practices in place to avoid COVID-19 infections, and (36.5%) of the study subjects had unfavorable habits regarding COVID-19 infection. Most students have a higher level of knowledge. The students did, however, have a moderate level of risk perception and satisfaction with the defeating role played by the educational institutions, teaching staff, and local health authorities. Peripheral government school students are better in terms of following and adhering to preventive measures. The knowledge of students in the first stage was significantly lower than those in other stages. Females gender and students with illiterate or read-and-write parents are more use of preventive measures. Females, aged <15, and students in the second and third grades are more satisfied with the preventive measures of their schools. There’s a big gap in the importance of the Corona vaccine.