After the 9/11 attacks, the United States has experienced a shift in its foreign policy strategy which was reflected in the U.S. National Security Strategy of 2002. In the NSS 2002, the United States security policies in particular put emphasis on issues of terrorism and nuclear proliferation. At the same time, in August 2002, the international public were surprised by the information that stated Iran has run an uranium enrichment facility and heavy water reactors. Responding to this fact, the United States firmly targeted Iran as "the axis of evil" that threatened the stability of international security with its nuclear program. Various efforts were launched by the United States to halt Iran's nuclear program. This research aims to explain U.S. foreign policy towards Iran's nuclear program during the George W. Bush administration (2002-2008). In addition, this research will also examine how the implementation of U.S. foreign policy and what factors that shape U.S. foreign policy towards Iran's nuclear program. The research is ongoing through the frame of mind that brings the concepts of foreign policy, national security, and national interests. The research approcah that will be used in this research is qualitative approach with historical method. Meanwhile, the techniques of data collection is using literature review and interview. The research data is obtained through the official websites of the United States government, various books about U.S. foreign policy, scientific research journals, official documents of the U.S. government, and also articles in scientific bulletins. The interview was conducted with the resource person, Drs. Alfian Muttalib, M.A. as a Lecturer of Universitas Nasional Kajian Wilayah Amerika as well as a national strategist from Pusat Pengkajian Strategi Nasional (PPSN). From this research, we can see that U.S. foreign policy towards Iran's nuclear program is affected by various factors ranging from changing perception of national security after the 9/11, the U.S. energy interests in the Middle East, concerns about the position of U.S. hegemony and the balance of power in the Middle East region.