Undoubtedly, HIV/AIDS menace has been a major source of concern to everyone, particularly, the people of Lower Manya Krobo Municipality (LMKM) as the area has always recorded a higher rate of infections compared with other districts in Ghana. Against this backdrop, the study sought to assess the HIV/AIDS knowledge of Senior High School students in the Lower Manya Krobo Municipality of the Eastern Region of Ghana. To obtain the respondents, a simple random sampling technique was adopted to select 300 students, comprising 120 boys and 180 girls proportionately selected from the four public Senior High Schools in the Municipality. A-37 item questionnaire adapted from Wanjiru Helen Wairimu was used for the data collection. The obtained data were analysed using descriptive statistics (means, standard deviations, frequencies, and percentages). The study found that the majority of the senior high school students in the LMKM of Ghana have high knowledge about HIV/AIDS through several available sources within their domain. However, it was again found out that HIV/AIDS knowledge they have does not have much impact and influence on their sexual behaviour. Several recommendations were suggested which include; the fact that the Ministry of Health in collaboration with other important educational agencies should intensify sex education to students and the community members in order to strengthen their awareness of HIV/AIDS.