Background: Human papillomavirus vaccination is a well-known global strategy for the prevention of cervical cancer. However, uptake of the vaccine varies between regions and countries of the world due to several discouraging factors. Although adolescents are at risk for cervical cancer, there are limited studies measuring human papillomavirus vaccination practice of adolescents among the study area. Objective: To assess human papillomavirus vaccination practice and its associated factors among secondary school female students in Nekemte town, Oromia region, Ethiopia, 2022 Methods and Materials: A school-based cross-sectional study was conducted from May 13 to June 13, 2022 among secondary schools female students in Nekemte town, Oromia region, Ethiopia. A total of 423 samples were selected using a computer generated simple random sampling technique. Data was collected using a structured and self-administered questionnaire. The study participants were informed of the need for this study. Epi Data version 4.6 was used for data entry and Statistical package for social science (version 25) for data analysis. Binary logistic regression was calculated using the odds ratio with a 95% confidence interval. Variables with a p-value < 0.25 in the bi-variable analysis were taken in to multi-variable analysis. Finally, variables with a p-value < 0.05 were declared as statistically significant. Result: The current study revealed that the prevalence of human papillomavirus vaccination practice was 52% (CI; 46.8-56.6) in the study area. Factors significantly associated with the human papillomavirus vaccination practice were: having good knowledge of human papillomavirus and its vaccine (AOR = 5.79, CI; 3.34 - 10.03), having positive attitude towards human papillomavirus vaccination (AOR = 8.36, CI; 4.67 - 14.93), higher level maternal education (college and above) (AOR = 5.47, CI; 1.68 - 17.82) and urban residence (AOR = 4.12, CI; 1.86 - 9.31). Conclusion and Recommendation: Prevalence of human papillomavirus vaccination practice was 52% in the study area. It was on average to the global strategy to eliminate cervical cancer in the target population. Knowledge, attitude, higher maternal educational level (college and above), and place of residence were associated with human papillomavirus vaccination. Therefore awareness creation and behavioral change education is necessary to enhance optimum coverage of the Vaccine. Keywords: female: Students, Human papillomavirus vaccination, Practice, Secondary School,