This study investigated facilitators and challenges to designing, implementing and evaluating school-based sexual health education in sub-Saharan Africa, using interviews with intervention designers and researchers. At the pre-planning and planning stages, participants reported that facilitating factors included addressing the reproductive health needs of participants, contextual (culture, religion, economic and social) considerations and the adoption of holistic approach to sexuality education. Lack of open communication about sexual health matters between young people and adults; concerns that sexual health education could encourage sexual activity; and inadequate funding, were key barriers. Implementation was facilitated by the involvement of relevant stakeholders, the training of facilitators and adopting strategies to overcome resistance to sexual health education. The provision of structured, detailed lessons plans and monitoring with supportive supervision optimised fidelity of delivery. Barriers to implementation included facilitators' resistance to teaching safe sex promotion and logistical challenges in school environments. Participants also reported that the validity of self-reported adolescent sexual behaviour (as part of evaluation) may be improved by complementing well-designed self-report surveys with computerised audio devices for data collection, qualitative interviews and participant observation. Study findings generate recommendations to improve future forms of school-based sexual health education in sub-Saharan Africa.