The purpose of this study is to investigate the mutual interactions between the causes of design changes using Interpretive Structural Modeling (ISM) and to classify the causes using the “Matrice d’Impacts Croisés Multiplication Appliquée à un Classement” MICMAC technique. This study further identifies and proposes strategies to mitigate design change occurrence and map them onto the identified connections between the causes. To achieve these goals, critical causes of design changes were identified through a comprehensive literature review; 23 key causes were then refined according to the opinions of relevant experts involved in the Iranian building construction sector. Stakeholders associated with each cause and the management areas from which causes arise were also considered. The factors “Unfamiliarity with new construction methods”, “Design errors”, “Value engineering”, “Scope uncertainty”, “Change orders”, and “Constructability ignored in the design phase”, which are highly influenced by other factors, emerged at the highest level of the ISM diagram, and “Clients’ attitudes and experience” as the main root cause of design changes at the bottom of the diagram. The MICMAC technique results showed that consultant-related causes significantly influence other causes, and policy and client-related causes have a feedback effect on the whole system. The findings of this study provide a better insight into how various causes of design changes are connected to one another and can ultimately assist project managers of different parties, even in other countries, to choose influential strategies to mitigate design changes in building construction projects.