INTRODUCTION Human papillomavirus (HPV) is one of the major causes of head and neck cancer (HNC). The incidence rate of newly diagnosed HPV-induced HNC cancer is on the rise, year-by-year; this is a problem of public health concern. This study aims to determine the prevalence and predictors of knowledge of senior secondary (high) school students in Nigeria on HPV and HPV vaccines. METHODS This study was a cross-sectional survey of 2530 high school students from six states in Nigeria using a selfadministered structured questionnaire. Data collected were analyzed using the SPSS version 25 software. RESULTS The mean (±SD) age of the respondents was 16.4 (±2.0) years, 56.0% were male and 34.9% were from the Yoruba ethnic group. Only 23.0% and 18.3% of the respondents were aware of HPV and HPV vaccine, respectively. The majority (78.2%) of those who were aware of HPV had below-average knowledge score about HPV. Those respondents: in the highest class in high school (AOR=1.36; CI=1.00-1.84; p=0.048); attending girls-only schools (AOR=2.86; CI: 1.93-4.24; p<0.001); and schooling in Bauchi state (AOR=2.56; CI: 1.47-4.51; p=0.001) were most likely to be aware of HPV compared to those in the other categories. However, those: attending girls-only (AOR=2.80; CI: 1.84-4.27; p<0.001); schooling in Bauchi state (AOR=2.87; CI: 1.55-5.33; p=0.001); and belonging to the Hausa tribe (AOR=2.41; CI: 1.51-3.85; p<0.001) were most likely to be aware to HPV vaccine than those in other categories. CONCLUSIONS The level of knowledge of HPV and HPV vaccine among high school students in Nigeria is very poor. There is a need for health education programs on HPV and HPV vaccines in Nigerian secondary schools.