Background: Reproductive health (RH) in adolescents and youth, as one of the critical components of population health policies, plays a pivotal role in preventing risky behaviors and achieving a healthy and productive generation for the future society. Thus, this study aimed to explore the challenges of RH in adolescents and youth in Iran. Methods: Using a purposeful sampling method with maximum variation, semi-structured in-depth interviews were held with eighteen key informants in the field of RH. A Snowball sampling strategy was deployed to identify the participants. The multi-dimensional PRECEDE-PROCEED model of health promotion was used as a guiding framework for the topic guide. The transcribed interviews were coded and analyzed using thematic analysis. Results: Three main themes of decision-making system, lifestyle, as well as social and epidemiological issues, were emerged from the interviews. We also explored six themes, including the knowledge and expertise about RH, policy-making and management system, environmental factors, individual factors, family and social anomalies, and epidemiological status of RH. Furthermore, twenty-five sub-themes were extracted from the main themes, which represented the challenges. Lack of understanding of the issues and absence of a coherent intellectual system that provides a collaboration of different systems in policy-making were fundamental and dominant challenges of RH for adolescents and youth in Iran. Conclusion: To meet these challenges, we require an integrated and coherent system of policy-making with a reliance on scanning individual, environmental, social, and epidemiological changes that influence RH.