Background: Unhygienic menstrual practices can affect the health of the girls and there is an increased vulnerability to reproductive tract infections and pelvic inflammatory diseases and other complications. OBEJECTIVE: To assess the menstrual hygiene practice and associated factors among female high school students in Motta town East Gojjam, Amhara Region Ethiopia 2021. METHODS: An institutional based cross-sectional study design was conducted from November 1 to November 30, 2021 in Motta town, East Gojjam Ethiopia. A total number of 571 female students were participated. Systematic random sampling technique was used to select the study participant. Data was collected by health extension workers by using self-administered questionnaires. The data was entered into EPI info and exported to (SPSS) version 23 software for analysis. Binary logistic regression was used to identify associated variables. Variable with p-value less than 0.05 in the multivariate analysis was considered as significant association with the menstrual hygiene practice. Result: The prevalence of safe menstrual hygiene management practice was 50.3% (95% CI: 46.2, 54.4). There are different factors which affect MHP. Student’s age 18-20 years and live in urban were 1.48 and 1.45 times more likely practice safe MHM than those counterparts (AOR=1.48; 95% CI: 1.02, 2.14; P=0.039) and (AOR=1.45; 95% CI: 1.01, 2.08.; P=0.043) respectively. Female high school adolescents who had positive attitude and good knowledge on MHM were (AOR=1.90; 95% CI: 1.06, 3.41; P=0.032), and (AOR=1.90; 95% CI: 1.31, 2.76, P=0.001) time more likely practice good MHM than their counterparts respectively. High school adolescents’ females who use sanitary or homemade pad for MHP and who learn about menstruation in the school were 1.44 and 1.94 times more likely to practice safe MH than those who use other materials and who did not who learn about menstruation in the school (AOR=1.44; 95% CI: 1.01, 2.04, P= 0.043) and (AOR=1.94; 95% CI: 1.21, 3.11.; P=0.006) respectively. Conclusion: More than half of the participants had safe level of menstrual hygiene practiced. Age, residence, types material used for MHM, knowledge and Attitude towards MHM were identified as the factors having stronger significant associated with the practices of menstrual hygiene in female students. Therefore, local government, health practitioners, the local Medias, school teachers and directors should do a lot to improve menstrual hygiene practice of female students in school levels. Key words: Menstruation, hygiene, practices, adolescent girls, secondary schools, Motta town.