In Ghana, youths aged 15–24 years constitute the group most vulnerable to HIV infection. Inadequate knowledge, negative attitudes and risky practices are major hindrances to preventing the spread of HIV. This study sought to investigate the knowledge, attitudes and practices regarding HIV/ AIDS among senior high school (SHS) students. Sekondi-Takoradi metropolis, Ghana. A descriptive, cross-sectional design was adopted, using a validated self-administered questionnaire, to collect data from a stratified sample of 294 senior students selected from three participating high schools in August 2017. The data collected were analysed using Stata version 12. Descriptive and inferential statistics were at a significance level of 0.05. Among the participants, 61.6% had good knowledge about HIV/AIDS, 172 (58.5%) showed positive attitudes towards people living with HIV (PLHIV) and 79.1% reported HIVrelated risky practices. We found a significant association between age and attitudes (p < 0.05). Poor knowledge was associated with being Muslim (aOR = 1.51 and 1.93; CI 1.19–1.91; p = 0.00) and being a student from school ‘F’ senior high school (F SHS) (aOR = 1.93; CI 1.71–2.18; p = 0.00). Bad attitude towards PLHIV and HIV was associated with ages 15–19 years (aOR = 3.20[2.58–3.96]; p = 0.03) p confirmed; and single marital status (aOR = 1.79[1.44–2.23]; p = 0.00). Bad practices were associated with ages 15–19 years (aOR = 1.72[1.41–2.11]; p = 0.08), belonging to the Akans ethnic group (aOR = 1.57[1.26–1.97]; p = 0.00) or being single (aOR = 1.79[1.44–2.23]; p = 0.00). Associations between misconceptions and HIV transmission were found: HIV can be transmitted by a handshake (aOR = 3.45[2.34–5.68]; p = 0.000), HIV can be cured (aOR = 2.01[2.12–5.04]; p = 0.004) and HIV/ AIDS can be transmitted by witchcraft (aOR = 3.12[3.21–7.26]; p = 0.001). Participants generally had inadequate knowledge regarding HIV/AIDS, manifested negative attitudes towards PLHIV and also engaged in risky practices that might predispose them to HIV transmission. Our findings underscore the need for culturally adapted and age-oriented basic HIV information for youths in the metropolis on misconceptions about HIV transmission, negative attitudes of students towards PLHIV as well as the risky practices of students regarding HIV.