Background The Dominican Republic (DR) has some of the highest rates of sexually transmitted infections (STI) and adolescent pregnancy in the Caribbean. Well-designed comprehensive sexuality education programs (CSEP) can reduce risky sexual behavior. This study sought to evaluate the Módulo Anexo Materno Infantil (MAMI) adolescent clinic’s CSEP in changing knowledge of STI and pregnancy and attitudes towards risky sexual behavior following implementation. Methods A mixed methods study was conducted among students aged 11–25 years from three schools between September 2017 and February 2018. Participants in MAMI CSEP completed questionnaires, before, immediately following, and 3 months following the CSEP. Questions assessed knowledge, attitude, and sexual experience, and obtained program feedback. There was one eight-participant focus group discussion (FGD) per school. Descriptive statistics summarized sample demographics and cross-sectional responses. McNemar’s test evaluated differences in the proportions of students selecting correct responses over time. Paired t-tests compared mean test scores across time. Result Overall response rate was 98.7% (1414/1432), with 486 pre-tests, 448 initial post-tests, and 480 3-month post-tests. Respondents identified as 53.5% (321/600) female and 46.5% (279/600) male with mean age of 14.2 years. More males (63.4%) reported sexual experience than females (35.8%) (p < 0.001). Increases in mean scores from pre-test to post-test and pre-test to 3-month post-test were statistically significant (p < 0.001). Three themes arose from the FGDs: (1) expanding sexual and reproductive health knowledge, (2) perception of curricular content, structure and delivery, and (3) student-health educator dynamic. Conclusion Improvement in test scores supports MAMI CSEP’s efficacy in educating students and reinforcing positive attitudes to reduce risky sexual behavior. Utilizing an interactive health educator model provided students with clear, accurate information in a safe environment with mutual trust. Selecting health educators employed by an adolescent clinic allows them to connect students to preventive and treatment services during the CSEP.