In March 1722, Isfahan fell to invading Afghan forces. The Ottomans, in collusion with the Russians, invaded western Iran, capturing Hamadan in 1724. In 1726, the Afghans killed Sultan Husayn. In 1729, just three years later, the forces of Sultan Husayn's son Tahmasb II, led by Nader Quli Bik of the Afshar tribe, one of the original Qizilbash tribes, retook Isfahan. They were welcomed by the city's population when they did. Domestic and even foreign powers had hoped and expected the Afghan ‘interlude’ to be brief, and it was. In 1732, Nadir deposed Tahmasb, in favour of the latter's infant son who, as Abbas III, ‘ruled’ for some four years. Nadir contracted marriages for himself and his son into the Safawid house, in the manner of the many earlier marriages between prominent Qizilbash tribal elements and members of the Safawid family, and in 1736 ascended the throne as Nadir Shah. He retook Qandahar from the Mughals in 1738–9, invaded India and, in 1740, executed both Tahmasb II and Abbas III.

Nadir's efforts to have the Ottomans recognise the Twelver faith as the ‘Jafari madhhab (school)’ alongside the four Sunni madhhabs – Hanafi, Shafii, Hanbali and Maliki – were more rooted in such practical goals as winning a peace with the Ottomans, which entailed their recognition of Iran's borders and their guarantee to safeguard Iranian pilgrims to the Hijaz more than they spoke to any fundamental disenchantment with the faith. Nadir was careful to devote considerable attention to, and designate as his new capital, Mashhad as well as the shrine cites in Iraq.