Abstract Background Delivered globally to promote adolescents’ sexual and reproductive health, comprehensive sex education (CSE) is rights-based, holistic, and seeks to enhance young people’s skills to foster respectful and healthy relationships. Previous research has demonstrated that CSE programmes that incorporate critical content on gender and power in relationships are more effective in achieving positive sexual and reproductive health outcomes than programmes without this content. However, it is not well understood how these programmes ultimately affect behavioural and biological outcomes. We therefore sought to investigate underlying mechanisms of impact and factors affecting implementation and undertook a systematic review of process evaluation studies reporting on school-based sex education programmes with a gender and power component. Methods We searched six scientific databases in June 2019 and screened 9375 titles and abstracts and 261 full-text articles. Two distinct analyses and syntheses were conducted: a narrative review of implementation studies and a thematic synthesis of qualitative studies that examined programme characteristics and mechanisms of impact. Results Nineteen articles met the inclusion criteria of which eleven were implementation studies. These studies highlighted the critical role of the skill and training of the facilitator, flexibility to adapt programmes to students’ needs, and a supportive school/community environment in which to deliver CSE to aid successful implementation. In the second set of studies (n = 8), student participation, student-facilitator relationship-building, and open discussions integrating student reflection and experience-sharing with critical content on gender and power were identified as important programme characteristics. These were linked to empowerment, transformation of gender norms, and meaningful contextualisation of students’ experiences as underlying mechanisms of impact. Conclusion and policy implications Our findings emphasise the need for CSE programming addressing gender and power that engages students in a meaningful, relatable manner. Our findings can inform theories of change and intervention development for such programmes.