The fall of the Safavid state in 1135 AH (1722 AD) has been a long-standing question in Iranian historiography. Contrary to conventional single-factor analyses, the present study argues that the relations and conduct of the Indian Mughals (Gurkanis), although not decisive in the dynasty’s final decline, intensified its weakening through four mechanisms: strategic competition over Kandahar, pressure on trade corridors, disruption of regional power equations, and the exacerbation of internal Safavid crises. Military confrontations between 1047 and 1062 AH (1638–1653 AD) not only drained the resources of both empires but also, by reproducing the historical pattern of domination over the “gates of India,” shifted the Safavid state’s focus from vital western and northern fronts to its eastern borders. Simultaneously, as alternative trade routes flourished in the Mughal realm and the flow of silk was redirected to southern ports, Safavid revenues declined. The widespread presence of Indian merchants (Baniyans) in Iran, along with their usurious activities and the resulting outflow of cash and coins, exacerbated the Safavid financial crisis. With the mutual weakening of the two powers in the second half of the 17th century, a power vacuum emerged on the eastern Iranian plateau, paving the way for the Hotak invasion and the eventual fall of Isfahan. Employing a descriptive analytical approach, this study shows that Iran–India relations during the Safavid and Mughal eras were marked by a dialectical bond of competition and dependence, which ultimately accelerated the decline of both empires and opened the path for the rise of the Afsharids and British colonialism in the subcontinent.