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Human papillomavirus (HPV) infection is implicated in causing several types of cancer, including cervical cancer. In Brazil, the quadrivalent HPV vaccine is provided free of charge for children between the ages of 9 and 14. Nevertheless, the vaccination coverage rate has remained below 60% since its implementation in 2014. This study aimed (i) to assess the knowledge of parents/guardians on HPV infection and vaccine prophylaxis and (ii) to test the association between having a “higher degree of knowledge” (HDK) and the sociodemographic characteristics. A total of 388 parents/guardians of children of vaccination age were enrolled. Questions assessing sociodemographic characteristics, knowledge, and attitudes toward HPV infection and vaccination were administered to participants via a self-answered questionnaire. Questionnaires of 343 participants were considered for analysis. Participants who answered at least 70% of the questions correctly were classified as presenting HDK. Multivariate logistic regression analysis was used to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs) for the associations between population characteristics and HDK. This study occurred prior to the COVID-19 pandemic; thus, the pandemic was not considered in our analysis. A total of 212 (61.8%) participants showed HDK. Participants who were male (OR = 0.39; 95% CI = 0.22, 0.70) and lived in larger households (OR = 0.48; 95% CI = 0.25, 0.95) were less likely to present HDK. Participants who reported having an acquaintance with prior/concurrent HPV infection were more likely to have HDK (OR = 3.78; 95% CI = 2.02, 7.05). These findings suggest the importance of developing novel strategies for raising parental awareness of HPV, particularly targeting males.