This study examined comprehensive knowledge of HIV (CKH) and its determinants among young people aged 15–24 years in Nigeria between 2003 and 2013. Secondary analysis was conducted on three rounds of NDHS 2003, 2008 and 2013 data. CKH increased significantly between 2003 and 2013, but the level reached in 2013 fell short of the global expectation for young people. Its significant determinants included gender, age, educational attainment, place and region of residence, household wealth status and uptake of HIV test. There is need to sustain all on-going effective youth-focused interventions and programmes to meet the comprehensive knowledge needs for all young people in Nigeria.