BackgroundSexually transmitted infections (STIs) are responsible for a high burden of morbidity and mortality in many developing countries especially among adolescents. Adolescents are predisposed to STIs because they are more likely to engage in unhealthy lifestyles. However, these adolescents have limited knowledge of the use and barriers to sexual and reproductive health information and care services. This study explored the knowledge of STIs among Senior High School Adolescents in the Wa Municipality of Ghana. MethodThe study designed as a descriptive cross-sectional research. A multistage sampling technique was used to recruit these adolescents for the study. Totally 355 adolescents were selected from senior high schools in the Wa Municipality. Descriptive statistics and Chi-square test were used to analyze the data, at a significance level of P < 0.05. ResultsThe majority of respondents had good knowledge of STIs, with the most common examples of STIs identified as HIV/AIDS (80.8%, 287/355) and gonorrhea (73.8%, 262/355). The main known signs and symptoms identified were discharges from the penis/vagina (72.4%, 257/355), painful urination (71.5%, 254/355), and itching, and sores around the genital area (72.7%, 258/355). The main sources of information/education of STIs for these adolescents were the school, hospital, internet and mother. Whom respondent lived with was found to be significantly associated with knowledge of STI (P < 0.001). ConclusionMany of the respondents had good knowledge of STI, and the school was the most common source of information on STI. It is, therefore, important for the Ghana Education Service and the Ghana Health Service to strengthen the School Health Education Programme in second cycle institutions in the Wa Municipality. Parents, especially mothers, should be actively involved in the sexual health education of adolescents.