This study explains the strategic model of the nuclear foreign policy of the Islamic Republic of Iran in confrontation with the United States based on the guidelines of the Martyr Imam, Ayatollah Khamenei (may Allah be pleased with him). Given the unilateral withdrawal of the United States from the JCPOA during the 12th Administration and the presidency of Donald Trump, the main issue is how to manage the crisis and identify the optimal strategy to protect national interests. The importance of the issue stems from the direct impact of the nuclear file on the country's security and international standing. The main question is what were the damages of Iran's nuclear policy during this period and what is the desired strategy based on the guidelines of the Martyr Imam. The research was conducted using a descriptive-analytical method, and game theory (with an emphasis on the concepts of zero-sum games, saddle points, and Nash equilibrium) was used as an analytical framework for operationalizing qualitative data and mathematical calculations of the interaction matrix. The analysis of the strategic interaction matrix between Iran and the United States and its comparison with the guidelines of Imam Shahid constitutes the main framework of the research. The results show that Imam Shahid's measures in the form of "active resistance" and "stepwise reduction of commitments" took the nuclear game out of the zero-sum state and created a new space for bargaining by creating a mixed Nash equilibrium. The results of the research, by combining game theory and Imam Shahid's guidelines, show that the indigenous model of nuclear policy guarantees national interests only by relying on the three principles of resistance, national dignity, and distrust of the enemy.