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Objective: This study aimed to evaluate the willingness of human papillomavirus vaccine and its associated factors in Dire Dawa in 2022. Ethiopia is undergoing human papillomavirus vaccine implementation in the country with the support of the Global Alliance for Vaccines and Immunization. However, there is a scarcity of data on problems encountered and the receiver’s acceptance of the vaccine. Methods: An institution-based cross-sectional study was conducted among 634 female adolescents from 1 April to 1 May 2022. A simple random sampling technique was used to select study participants. Pretested structured self-administered questionnaires were used to collect data. Data were entered into EPI-data 3.1 and exported to Statistical Package for the Social Sciences version 23.00 software for analysis. Descriptive analysis was conducted to summarize data with text, tables, and figures. A binary logistic regression model was fitted to identify factors associated with the willingness of the human papillomavirus vaccine. Adjusted odds ratios with 95% confidence intervals and p -values less than 0.05 were used to determine the association between independent and dependent variables. Hosmer and Lemeshow test was used to determine model fitness. Results: The magnitude of human papillomavirus vaccine willingness among adolescent girls was 56% with 95% CI (52.1%–59.9%). Discussion on sexual and reproductive health issues (AOR = 7.67, 95% CI: 3.82, 15.42), adolescent girls who were received permission from their family to take human papillomavirus vaccine (AOR = 4.49, 95% CI: 2.40, 8.43), adolescent girls who had good knowledge on human papillomavirus vaccine (AOR = 5.78, 95% CI: 3.18, 10.15), and adolescent girls who had favorable attitude toward human papillomavirus vaccine (AOR = 3.06, 95% CI: 1.73, 5.43) were positively associated with willingness to take human papillomavirus vaccine. Conclusion: Knowledge about cervical cancer and the human papillomavirus vaccine as well as willingness to take the human papillomavirus vaccine was low. Factors such as maternal education, adolescents’ discussion on sexual and reproductive health issues, parent approval of human papillomavirus vaccine, and knowledge and attitude toward human papillomavirus vaccine were significantly associated with willingness to take the human papillomavirus vaccine. Therefore, public health education regarding cervical cancer and human papillomavirus vaccination is still needed and has to be targeted at not only respondents but also their families.