Cervical cancer is the ninth most common cancer among women in Saudi Arabia, with human papillomavirus (HPV) infection being the primary risk factor. One of the major strategies for prevention is vaccination, and parental consent is crucial for HPV vaccination, particularly for girls aged 9 to 14. However, studies on parental acceptance and the barriers to HPV vaccination for minors in Asir, Saudi Arabia, are limited, indicating the need for further research. This cross-sectional study utilized an online questionnaire platform from March 2023 to November 2023 in Asir, Saudi Arabia, collecting data from 539 parents of daughters under 18. Various demographic variables were assessed to determine their impacts on vaccine acceptance. The study aimed to evaluate parental acceptance, knowledge, and barriers related to HPV vaccination in the region. The findings revealed an acceptance rate of 65.9% for the HPV vaccine among parents. Significant factors influencing acceptance included age, with 45-54 age group exhibiting the lowest acceptance rate of 54.4% ( = .007). Additionally, healthcare worker status impacted acceptance, with a higher rate of acceptance among healthcare workers (76.7%) compared to non-healthcare workers (62.3%) ( = .002). The study also uncovered considerable knowledge gaps, as evidenced by a mean knowledge score of only 24.18%. Acceptance rates appeared to increase with higher education levels (OR = 2.68, 95% CI: 1.08-6.63,  = .033), having a single daughter under 18 (OR = 2.25, 95% CI: 1.16-4.35,  = .016), receiving recommendations from the Ministry of Health (OR = 6.07, 95% CI: 2.43-15.20,  < .001), and knowing friends or relatives who have been vaccinated (OR = 6.75, 95% CI: 3.72-12.24,  < .001). In conclusion, this study found that education and the source of information regarding the HPV vaccine significantly influence parental acceptance. The results support the need for targeted education intervention programs to promote HPV vaccination among parents.