South Khorasan Province is split into two distinct regions: the "mountainous and elevated" areas in the north and northwest, and the "low and flat" central and southern plains.

The northern and northwestern parts are more fertile, while the southern and southwestern plains endure a dry and harsh climate.

Esfarayen, among other cities of the province, was one of the focal points for the residence of the Aryan tribes after entering Iran.

Khorasan was divided into four parts during the Muslim conquest of Persia, each section being named after the four largest cities, Nishapur, Merv, Herat, and Balkh.

Mahmud of Ghazni retaliated against the invaders several times, and finally the Ghaznavids defeated Sultan Sanjar.

In the 14th century, a flag of independence was hoisted by the Sarbedaran movement in Sabzevar, and in 1468, Khorasan came into the hands of Tamerlane and the city of Herat was declared as the capital.

In these periods, Birjand was a small part of Quhistan which almost encompasses the borders of today South Khorasan.

This region was a place of refuge for some movements like the Ismaili, and was the target of Arab refugees who escaped from the tyranny of the Abbasid caliphate.

In 1856, the Persians launched another invasion, and briefly managed to recapture the city; it led directly to the Anglo-Persian War.

However, historically Qohistan forms a separate entity, with a distinct culture, history, environment and ecology.

The population history and structural changes of South Khorasan province's administrative divisions over three consecutive censuses are shown in the following table.