The river's source lies in the Mongolian Altai in Dzungaria (the northern part of Xinjiang, China) close to the border with Mongolia.

The largest tributaries of the Irtysh are, from source to mouth: In Kazakhstan and Russia, tankers, passenger ships, and cargo vessels navigate the river during the ice-free season, between April and October.

The Northern river reversal proposals, widely discussed by the USSR planners and scientists in the 1960s and 1970s, would send some of the Irtysh's (and possibly Ob's) water to the water-deficient regions of central Kazakhstan and Uzbekistan.

[7] While these gigantic interbasin transfer schemes were not implemented, a smaller Irtysh–Karaganda Canal was built between 1962 and 1974 to supply water to the dry Kazakh steppes and to one of the country's main industrial center, Karaganda.

[9][10] According to a report published by Kazakhstan fishery researchers in 2013, the total Irtysh water use in China is about 3 cubic kilometres (0.7 cu mi) per year; as a result, only about 2/3 of what would be the river's "natural" flow (6 km3 out of 9 km3) reach the Kazakh border.

[15] In the 17th century the Dzungar Khanate, formed by the Mongol Oirat people, became Russia's southern neighbor, and controlled the upper Irtysh.

[16] As a result of Russia's confrontation with the Dzungars in the Peter the Great's era,[17] the Russians founded the cities of Omsk in 1716, Semipalatinsk in 1718, Ust-Kamenogorsk in 1720, and Petropavlovsk in 1752.

This prompted an increase in the Russian authorities' attention to their borderland; in 1756, the Orenburg Governor Ivan Neplyuyev even proposed the annexation of the Lake Zaysan region, but this project was forestalled by Chinese successes.

In the summer of 1828, the Prussian explorer Alexander von Humboldt visited the Irtysh region on his journey through Russia and Central Asia; he came face-to-face with Chinese and Mongol border guards.

After the fall of the rebellion and the reconquest of Xinjiang by Zuo Zongtang, the border between the Russian and the Qing empires in the Irtysh basin was further slightly readjusted, in Russia's favor, by the Treaty of Saint Petersburg (1881).

In Aleksandr Solzhenitsyn's The GULAG Archipelago, the chapter "The White Kitten" details Georgi Tenno's escape from a camp along this river.