AbstractBackground and AimsThe human papillomavirus (HPV) vaccination has shown considerable promise in lowering the incidence of cervical cancer. However, there are few studies done on knowledge and attitude toward the HPV vaccine, especially in the local setting. Therefore, this study aimed to assess knowledge and attitudes regarding HPV vaccination and related factors among adolescent girls in Ambo town, Ethiopia, in 2021.MethodsA cross‐sectional study was conducted from May 1 to May 30, 2021, at selected schools in Ambo town among 422 adolescent girls. A structured self‐administered questionnaire was used to collect the data. The collected data were coded, and entered into Epi‐Info 7.2.2.6 and exported to STATA 16 for analysis. Descriptive statistics were used to compute summary statistics and proportions. Bivariate and multivariate logistic regression analyses were carried out. The adjusted odds ratio (AOR) along with a 95% confidence interval (CI) was computed to ascertain the association.ResultsCurrent study revealed that 24.9% (95% CI: 20.8–29.0) and 55.6% (95% CI: 50.5–60.4) of respondents had good knowledge and favorable attitude, respectively. The factors like being secondary school students [AOR = 2.01, 95% CI; (1.24, 3.27)], having health workers as a source of information [AOR = 2.13, 95% CI; (1.30, 3.47)], and respondents who have heard about the HPV vaccine at school [AOR = 1.66, 95% CI; (1.02, 2.71)] were significantly associated with respondent's knowledge of HPV vaccine. Moreover, the perceived severity of the diseases [AOR = 2.89, 95% CI; (1.61, 5.21)], and the perceived benefit of the vaccine [AOR = 4.26, 95% CI; (2.43, 7.48)] were factors significantly associated with an attitude of the respondents about the HPV vaccine.ConclusionThere was low knowledge and unfavorable attitude toward HPV vaccination among the school adolescents in the study area. Several seemingly major deterrents of knowledge and attitude toward the HPV vaccination were identified. Therefore, all parties involved should collaborate to improve female students' knowledge and attitudes toward Human Papilloma Virus vaccination.