Islamic Resistance, as one of the strategic concepts in the discourse of the Islamic Revolution, is based on principles rooted in Quranic teachings and the Prophetic tradition (Sirah). The present research is conducted with the aim of identifying and analyzing the epistemological foundations of Islamic Resistance in the thought of Ayatollah Khamenei. In this study, by emphasizing the concept of “Nafi al-Sabil” (negation of domination) and the necessity of standing against the hegemony of the domination system, the epistemological and insightful foundations of Islamic Resistance have been examined. The findings indicate that reliance on Divine power (Tawakkul), acceptance of Wilayat (guardianship), self-sacrifice, human dignity, and support for the oppressed are not merely ethical principles but epistemological foundations that play a significant role in strengthening the individual and collective spirit of resistance. Ayatollah Khamenei’s statements also indicate that these foundations are among the key pillars of the school of Islamic Resistance and can pave the way for sustainability, progress, and effective confrontation with internal and external challenges. This research attempts to provide new horizons for cultural policymaking and the consolidation of Islamic identity in Muslim societies by explaining the epistemological foundations of resistance