The ultimate source of the Indus is on the Tibetan plateau in the vicinity of Lake Mansarovar; it begins at the confluence of the Sengge and Gar rivers that drain the Nganglong Kangri and Gangdise Shan mountain ranges. The Indus then flows northwest through Ladakh-Baltistan into Gilgit, just south of the Karakoram range. The Shyok, Shigar and Gilgit streams carry glacial waters into the main river. It gradually bends to the south, coming out of the hills between Peshawar and Rawalpindi.

The Indus passes gigantic gorges 4500 - 5200 meters (15,000-17,000 feet) high near the Nanga Parbat massif. It swiftly flows across Hazara and is dammed at the Tarbela Reservoir. The Kabul River joins it near Attock. The remainder of its route to the sea is in plains of the Punjab and Sindh, where the river becomes slow-flowing and highly braided. It is joined by Panjnad River at Mithankot. Beyond this confluence, the river, at one time, was named the Satnad River (sat = seven, Nadi = river) as the river was now carrying the waters of Kabul River, Indus River, and the five Punjab rivers. Passing by Jamshoro, it ends in a large delta to the east of Thatta, near Pakistan's port city, Karachi. The total length of the river is 3200 kilometers (2000 miles).

The river has a total drainage area exceeding 1,165,000 square kilometers (450,000 square miles). Its estimated annual flow stands at around 207 cubic kilometers. Beginning at the heights of the world with glaciers, the river feeds the ecosystem of temperate forests, plains and arid countryside. Together with the rivers Chenab, Ravi, Sutlej, Jhelum, Beas, and the extinct Sarasvati River, the Indus forms the ("Seven Rivers") delta in the Sindh province of Pakistan.

It has 20 major tributaries. The Indus is one of the few rivers in the world that exhibits a tidal bore. The Indus system is largely fed by the snows and glaciers of the Karakoram, Hindu Kush and Himalayan ranges of Tibet, Kashmir, and Northern Areas of Pakistan. The flow of the river is also determined by the seasons; it diminishes greatly in the winter while flooding its banks in the monsoon months from July to September.

There is also evidence of a steady shift in the course of the river since prehistoric times; it has deviated westwards from flowing into the Rann of Kutch. The Indus provides the key water resources for the economy of Pakistan, especially the breadbasket of Punjab province, which accounts for most of the nation's agricultural production, and Sindh. It also supports many heavy industries and provides the main supply of potable water in Pakistan.