Background: Human papillomavirus (HPV) vaccine is a prophylactic HPV vaccine developed to prevent the most common high-risk strains and low-risk infections of human papilloma virus. Human Papilloma Virus (HPV) oncogenic or high-risk sexually transmitted strains account for more than 99% of cervical cancer cases. However, it’s a preventable form of cancer through the HPV vaccine. This protects against the most prevalent strains of high-risk and low-risk human papillomavirus infection. Objective: To assess the Knowledge, attitude, practice and associated factor about human papillomavirus vaccine among female secondary school students at Hawassa city, sidama region, Ethiopia, 2023 G.C Methods and materials:-A school -based cross sectional study was conducted from February 2023 - to - May 2023 G.C. Data was collected by interview based questionnaires prepared on kobo tool box data base and collected by ODK application.The sample size for this study is 692. Participants were selected by using multi-stage sampling approach. Data was collected by ODK application and it was exported to SPSS version 26 for analysis. Logistic regression was applied and odd ratios were calculated to determine strength of association. Results was interpreted as association if p-value < 0.05 at 95% CI. Result: A total of 661 students participated in the study with a response rate of 95.5%. Among participants in this study, 52.2 % have good knowledge, 47.8% have positive attitude and 60.7% good practice towards HPV vaccine. The factors associated with the practice of vaccination were; being knowledgeable about HPV vaccination (AOR= 4.097, 95% CI=2.7- 6.13) and a positive attitude towards HPV vaccination (AOR=1.72, 95% CI=1.08–2.76). Students family residence in urban (AOR= 2.68, 95% CI=1.64- 4.36) and information about HPV vaccination (AOR=4.63, 95% CI=2.97- 7.21). Conclusion and recommendation: Overall, study participants 52.2 % have good knowledge, 47.8% have positive attitude and 60.7% good practice towards HPV vaccine. Knowledge on HPV vaccination, positive attitude towards HPV vaccination, family residence being urban and information about HPV vaccination were associated with HPV vaccination practice. An integrated work on attitude change and focusing on improve the knowledge about HPV vaccine on eligible group female students.