A Humanitarian supply chain deals with the delivery of supplies to the population of areas affected by natural disasters. One of the most important issues in Humanitarian Supply Chain Management (HSCM) is identifying and structuring different challenges and barriers in relief chains. This study is an attempt to provide a comprehensive framework for HSCM challenges in a case study of the Iranian Red Crescent Society (IRCS). We identify HSCM challenges through literature review and expert opinions and use Fuzzy Delphi Method (FDM) to select the most important challenges. Fuzzy Interpretive Structural Modeling (FISM) is then used to map the cause and effect relationships among various factors and develop a holistic picture of the main HSCM challenges. Finally, the overall framework of the HSCM challenges and the hierarchical model of the FISM are statistically verified using the Partial Least Square (PLS) method. We identify “managerial challenges” (at the category level), and “unfamiliarity of top managers with management knowledge” and “inappropriate division of labor” (at the sub-challenges level) as the root sub-challenges in this case study. Challenges not handled properly in pre-disaster stage will most likely occur more drastically in the post-disaster stage of the operations. The proposed model provides insightful guideline for increasing the effectiveness of relief efforts.