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In addition to fighting its perennial enemies, the Ottomans and Uzbeks, as the 17th century progressed Iran had to contend with the rise of two more neighbors. Russian Muscovy in the previous century had deposed two western Asian khanates of the Golden Horde and expanded its influence into the Caucasus Mountains and Central Asia. In the east, the Mughal dynasty of India had expanded into Afghanistan at the expense of Iranian control, taking Qandahar. Furthermore by the 17th century, trade routes between the East and West had shifted away from Iran, causing a loss of commerce and trade. Moreover, Shah Abbas had a conversion to a ghulam-based military, though expedient in the short term. Except for Shah Abbas II, the Safavid rulers after Abbas I were ineffectual. The end of his reign, 1666, marked the beginning of the end of the Safavid dynasty. Despite falling revenues and military threats, later shahs had lavish lifestyles. Shah Soltan Hosain (1694-1722) in particular was known for his love of wine and disinterest in governance.

The country was repeatedly raided on its frontiers - Kerman by Baloch tribesmen in 1698, Khorasan by Afghans in 1717, constantly in Mesopotamia by peninsula Arabs. Shah Sultan Hosein tried to forcibly convert his Afghan subjects in eastern Iran from Sunni to the Shi'a sect of Islam. In response, a Ghilzai Pashtun chieftain named Mir Wais Khan began a rebellion against the Georgian governor, Gurgin Khan, of Kandahar and defeated the Safavid army. Later, in 1722 an Afghan army led by Mir Wais' son Mahmud marched across eastern Iran, besieged, and sacked Isfahan. Mahmud proclaimed himself 'Shah' of Persia. The Afghans rode roughshod over their conquered territory for a dozen years but were prevented from making further gains by Nadir Shah, a former slave who had risen to military leadership within the Afshar tribe in Khorasan, a vassal state of the Safavids. Nadir Shah defeated the Afghans in the Battle of Damghan, 1729. He had driven out the Afghans, who were still occupying Persia, by 1730. In 1738, Nadir Shah reconquered Eastern Persia, starting with Qandahar; in the same year he occupied Ghazni, Kabul, and Lahore, later conquering as far as east as Delhi, but not fortifying his Persian base and exhausting his army's strength. He had effective control under Shah Tahmasp II and then ruled as regent of the infant Abbas III until 1736 when he had himself crowned shah. Immediately after Nadir Shah's assassination in 1747, the Safavids were re-appointed as shahs of Iran in order to lend legitimacy to the nascent Zand dynasty. However the brief puppet regime of Ismail III ended in 1760 when Karim Khan felt strong enough take nominal power of the country as well and officially end the Safavid dynasty.

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