Background. Cervical cancer is Ethiopia’s second biggest cause of cancer-related death among women. The introduction of human papilloma virus (HPV) vaccination is expected to have a significant impact on the burden of cervical cancer. In Ethiopia, particularly in our study area, little is known regarding girls’ acceptance of HPV vaccination. Therefore, this study has assessed the acceptance of HPV vaccination and associated factors among girls in Arba Minch town, southern Ethiopia. Methods. A school-based cross-sectional study was conducted on January 1, 2020. Based on convenience, Arba Minch town was purposefully selected. Stratification was done to stratify private and public schools, then simple random sampling to select sample schools from each, and finally, a proportional allocation of sample size to each school. The determinants and independent variables that influence the acceptance of the human papillomavirus vaccination were determined using a multivariable logistic regression model. Results. This study’s overall acceptance rate for study participants was 50.4% (95% CI) (45.9–55.2). Girls’ age (