In Senegal, school-based sexuality education has evolved over 20 years from family life education (FLE) pilot projects into cross-curricular subjects located within the national curriculum of primary and secondary schools. We conducted a literature review and semi-structured interviews to gather information regarding the scale and nature of FLE scale-up. Data were analysed using the ExpandNet/WHO framework, conceptualising scale-up from a systems perspective as composed of interrelated elements and strategic choices. Key enabling factors that facilitated the scale-up of FLE included (1) programme clarity, relevance and credibility; (2) programme adaptability to young people’s evolving sexual and reproductive health priorities; (3) the engagement of a strong and credible resource team comprising government and civil society agencies; (4) a favourable policy environment; and (5) deliberate strategic choices for horizontal and vertical scale-up. Barriers included sociocultural conservatism that creates resistance to content areas deemed to be culturally sensitive, resulting in partial scale-up in terms of content and coverage, as well as structural barriers that make it difficult to find space in the curriculum to deliver the full programme. Lessons learned from Senegal’s experience can strengthen efforts to scale-up school-based sexuality education programmes in other culturally conservative low- and middle-income countries.