The 1,576 kilometres (979 mi) long Kafue River is the longest river lying wholly within Zambia. Its water is used for irrigation and for generating hydroelectric power. It is the largest tributary of the Zambezi, and of Zambia's principal rivers, it is the most central and the most urban. More than 50% of Zambia's population live in the Kafue River Basin and of these around 65% are urban.

It has a mean flow rate of 320 cubic metres per second (11,000 cu ft/s) through its lower half, with high seasonal variations. The river discharges 10 cubic kilometres (2.4 cu mi) per year into the Zambezi River.

The Kafue River rises at an elevation of 1,350 metres (4,430 ft) on the relatively flat plateau just south the border between Zambia and the Democratic Republic of the Congo 120 kilometres (75 mi) north-west of Chingola in the Copperbelt Province. The source of the Kafue River is in the North-western Province of Zambia. The area is Miombo woodland on the Congo-Zambezi watershed, with many branching dambos lying 10 to 20 metres (33 to 66 ft) lower than the highest ground, producing a very gently undulating topography. The river starts as a trickle from the marshy dambos (the Munyanshi Swamp is a tributary) and with little slope to speed up river flow, it meanders south-eastwards sluggishly and within 50 kilometres (31 mi) has the character of a mature river. The area receives about 1,200 millimetres (47 in) of rain in the rainy season, and the river's channel soon reaches 100 metres (330 ft) wide with a floodplain of fluvial dambos 1 to 2 kilometres (0.62 to 1.24 mi) wide.

Before the river reaches the Copperbelt towns, however, it loses its wide floodplain, the channel narrows to 30–40 m and it meanders less, in a shallow valley only 40 m or so lower than the surrounding plateau. It flows close to the Copperbelt towns of Chililabombwe, Chingola and Mufulira, and through the outskirts of Kitwe. The popular picnic spot the Hippo Pool north of Chingola is protected as a national monument.

In the Copperbelt, water is taken from the river to irrigate small farms and market gardens. At Kitwe it changes course to the south-west and flows through forest and areas of flat rock over which it floods in the wet season, keeping to a channel about 50 m wide in the dry season.

The river again develops intricate meanders and a maze of channels in a swampy floodplain, with oxbow lakes and lagoons. It flows 20 km west of the permanent part of the Lukanga Swamp which fills a circular depression, and which drains through a channel into the Kafue. The area between the swamp and river is flood plain and when that and surrounding areas are inundated in the rainy season, the combined wetland exceeds 6,000 km². This is the first of the three main wildlife areas of the river, and the least surveyed and protected.

The character of the river changes again, as it forms a less meandering dry-season channel with sandy banks and islands. Continuing south-west it enters the Kafue National Park, second largest national park in Africa, where it receives its two largest tributaries, the Lunga and Lufupa rivers, also from the north. The Kafue skirts the south-east edge of the Busanga Plain, one of Africa's premier wildlife areas, known for large herds of cape buffalo, zebra and antelope. In the rainy season the Lufupa floods the plain.

Like the upper Zambezi, Okavango and Cuando rivers, the Kafue used to flow south all the way to Lake Makgadikgadi and on to the Limpopo River, but the land in that area was uplifted. A rift valley formed running due east of where the Kafue National Park is now, and the Kafue river eroded a channel called the Itezhi-Tezhi Gap through a ridge of hills about 100 m high, flowing eastwards. The Itezhi-Tezhi Dam was built in 1977 at the gap and now forms a reservoir 50 km long and up to 10 km wide.