In Nigeria, adolescents have been long identified as vulnerable to sexually transmitted infections (STIs) including HIV/AIDS. They face multiple challenges including unwanted pregnancies, unsafe abortion, sexual coercion resulting in sexually transmitted infections including HIV and AIDS. The study assessed sexual behavior and knowledge of reproductive health and HIV prevention among secondary school students as part of efforts to plan appropriate interventions among this population. The study employed a cross-sectional study design in which data were collected from 1914 secondary schools students across six states in all the geopolitical zones in Nigeria. Data were collected using 47 item questionnaire which explored the students’ socio-demographic characteristic, knowledge of HIV/AIDS and reproductive health, attitude towards HIV prevention and people living with HIV/AIDS, condom use and abstinence and sexual behaviour. Data was analysed using descriptive statistics, Chi-square and t-test at 0.05 level of significance. Majority (93.6%) of the respondents had good knowledge of HIV and other STIs. Females had a slightly higher mean knowledge of HIV and other STIs than their male counterparts (38.4 ±7. 7 vs 37.8 ± 7.5) (p<0.05). Only 22.8% has ever been tested for HIV out of which 25.5% were males and 20.5% were females. More males (24.4%) reported that they had ever experienced sexual intercourse than their female counterparts (13.2%). The overall mean age of sexual debut was 13.9 ± 4.9. Secondary schools students in Nigeria are quite knowledgeable about reproductive health but few practice safe sex. Behavioral change communication needs to be strengthened among these adolescents. Keywords: HIV/AIDS, reproductive health, sexual behaviour, adolescent, sex