However, Russian colonization of the region only began in the 18th century, with the establishment of a system of fortresses and trade posts on the then-Russian border by the Orenburg Expedition [ru] in 1734.

The period from the 1750s to the 1770s saw the emergence of industrial enterprises in the Southern Urals when the first factory-centered towns like Miass, Kyshtym, and Zlatoust were founded.

After the Southern Urals recovered from the Pugachev's Rebellion of 1773–1775, the territory of modern-day Chelyabinsk Oblast started to attract more people from the European part of Russia.

By the mid-19th century Chelyabinsk was a major trade center in the Urals, and after the construction of the Trans-Siberian Railway in the 1890s, it became an important transport hub that connected Siberia to the rest of the Russian Empire.

The economy continued to grow after the outbreak of the Great Patriotic War in 1941, as industries evacuated from the western parts of the Soviet Union to the Urals, and to Chelyabinsk Oblast in particular.

While there are no nuclear power stations in Chelyabinsk, a number of production reactors were located there starting with the early Cold War.

Sławomir Grünberg has made the documentary Chelyabinsk: The Most Contaminated Spot on the Planet (1994) about the unsafe dumping of radioactive waste in the Techa River and in Lake Karachay.

On 4 July 1997, Chelyabinsk, alongside Bryansk, Magadan, Saratov, and Vologda signed a power-sharing agreement with the government of Russia, granting it autonomy.

Health officials said 112 people had been hospitalized, mainly from injuries caused by glass from windows shattered by a shock wave; two were reported to be in serious condition.

The meteor created a dazzling light as it air burst, bright enough to cast shadows during broad daylight in Chelyabinsk.

This boundary is marked by a stone pillar at the Uraltau pass near the Urzhumka station (8 km (5.0 mi) from Zlatoust), which has "Europe" written on one side and "Asia" on the other.

The highest point of Chelyabinsk Oblast, reaching 1,406 metres (4,613 ft) above sea level, is located in the Nurgush, a 50 kilometres (31 mi) long mountain range rising near lake Zyuratkul.

Seven rivers, the Miass, Uy, Ural, Ay, Ufa, Uvelka, and Gumbeyka, pass through the area and are longer than 200 km (124 mi).

Chelyabinsk Oblast is also home to more than 3,748 lakes, mostly located in the north and east and covering a total area of 2,125 km2 (820 sq mi).