Safi was crowned on 28 January 1629 at the age of eighteen. He ruthlessly eliminated anyone he regarded as a threat to his power, executing almost all the Safavid royal princes as well as leading courtiers and generals. He paid little attention to the business of government and had no cultural or intellectual interests (he had never learned to read or write properly), preferring to spend his time drinking wine or indulging in his addiction to opium.

The dominant political figure of Safi's reign was Saru Taqi, appointed grand vizier in 1634. Saru Taqi was incorruptible and highly efficient at raising revenues for the state, but he could also be autocratic and arrogant.

Iran's foreign enemies took the opportunity to exploit Safi's perceived weakness. Despite firm initial Safavid successes and humiliating defeats in the Ottoman–Safavid War (1623–1639) by Safi's grandfather and predecessor Shah Abbas the Great, the Ottomans, having had their economy and military stabilized and reorganized under Sultan Murad IV made incursions in the west in one year following Safi's ascension to the throne. In 1634 they briefly occupied Yerevan and Tabriz and in 1638 they finally succeeded in recapturing Baghdad Reconquest of Baghdad (1638) and other parts of Mesopotamia (Iraq) which, despite being taken again several times later on in history by the Persians and most notably by Nader Shah, it would all remain in their hands until the aftermath of World War I. Nevertheless, the Treaty of Zuhab which ensued in 1639 put an end to all further wars between the Safavids and the Ottomans. Apart from the Ottoman wars, Iran was troubled by the Uzbeks and Turkmens in the east and briefly lost Kandahar in their easternmost territories to the Mughals in 1638, due to what seems as an act of revenge by their own governor over the region, Ali Mardan Khan, after being dismissed from office.