During the Safavid era, three significant events occurred in the Persian Gulf, impacting the situation of this vital waterway and its littoral inhabitants. First, the arrival of the Portuguese in the Persian Gulf and Hormuz Island in the 10th century AH/16th century AD; second, the collapse of Portuguese maritime dominance and the entry of the English and Dutch East India Companies into the Persian Gulf in the 11th century AH/17th century AD; and the third event took shape in the 12th century AH/18th century AD with the incursions of Muscat Arabs and the phenomenon known as piracy, which subjected the Persian Gulf to numerous tensions and conflicts. All three events are related to the presence of trans-regional powers in this crucial waterway. The main objective of this article is to examine and analyze the Safavid government's policy regarding these three events in the Persian Gulf arena, its engagement with the influential trans-regional powers in this waterway, and the subsequent consequences for the state, which spurred a form of international political and commercial interaction for the Safavid government. The research findings indicate that the Safavid policy towards the developments in the Persian Gulf fluctuated from a passive policy of accepting the status quo in the 10th century AH/16th century AD to an active, offensive, and opportunity-seizing policy during the era of Shah Abbas I (995-1038 AH/1587-1629 AD), and subsequently to an unstable and chaotic policy in the late Safavid period.