The São Francisco River rises at about 2,400 feet (730 metres) above sea level on the eastern slope of the Serra da Canastra in southwestern Minas Gerais state, about 150 miles northwest of the city of Belo Horizonte. The river flows for more than 1,000 miles northward across the states of Minas Gerais and Bahia, through the extensive Sobradinho Reservoir, to the twin cities of Juàzeiro (Juazeiro) and Petrolina. In this stretch the river receives its main left-bank tributaries—the Paracatu, Urucuia, Corrente, and Grande rivers (Grande River)—and its main right-bank tributaries—the Verde Grande, Paramirim, and Jacaré.

About 100 miles below Petrolina, the São Francisco begins a great curve to the northeast and enters a stretch of rapids and falls 300 miles long. In this section the river forms the border between the states of Bahia to the south and Pernambuco to the north. The upper rapids are navigable during periods of high water, but below Petrolina the river is impassable. The broken course—during which the São Francisco receives the São Pedro, Ipueira, and Pajeú rivers—culminates in the great Paulo Afonso Falls. At the top of the falls, the river divides suddenly and violently and cuts three successive falls through the granite rocks for a total drop of about 275 feet. Below the falls the river flows about 190 miles to its relatively narrow mouth on the Atlantic Ocean, about 60 miles northeast of Aracaju. In its lower section the São Francisco is joined by the Moxotó River and forms the border between the states of Sergipe to the south and Alagoas to the north.

The lower river basin is largely a tropical semidesert, and the climate generally is hot and dry. The average maximum temperature for the region is 92° F (33° C) and the average minimum 66° F (19° C). The highest temperature recorded is 107° F (42° C). The prevailing winds are from the southeast, east, and northeast. Rainfall is deficient over most of the area, and drought is frequent. Average annual precipitation measures 20 to 40 inches (510 to 1,020 millimetres) in most of the middle basin and 40 to 80 inches in the headwaters region and below the Paulo Afonso Falls; most of the falls zone receives less than 20 inches annually, and a small portion receives less than 10 inches. Precipitation occurs during the summer months (December to March), while the rest of the year—the winter season—is dry.

Because the São Francisco River flows through the driest region of Brazil, it is subject to seasonal changes in water level of up to 30 feet. Most of its tributaries run dry during the dry season. Until the river was dammed at Juàzeiro, the riverbed upstream from there would vary from a narrow channel during drought periods to a much wider channel during the rainy season; the Sobradinho Reservoir now holds water throughout the year, although its level can vary considerably.

The upper (southern), relatively wet part of the basin is covered with savanna (grassland with patches of trees), called cerrados, and with forests of mixed evergreen and deciduous trees. Hardwoods include the jacaranda, Brazilian cedar (cedro), and vinhatico; cochineal cactus, aloes, and vanilla plants also grow there. Characteristic of the middle river basin is caatinga vegetation (from the Tupí-Guaraní word meaning “white forest”), an area of stunted, often thorny forest. Among the dominant tree species are the leguminous catingueiras and juremas, members of the euphorbia (spurge) family, and the barriguda tree (a palmlike tree of the Bombacaceae family); bromeliads (plants with basal, often spiny leaves) and a wide variety of cacti constitute the undergrowth. Economically useful species include the caroa, used for its fibres; the castor oil plant; oil, carnauba, and date palms; and cashew and rubber trees.

The falls zone lies in the dry Brazilian interior, known as the sertão. The small amount of rainfall in the area permits the growth of only xerophytic (drought-resistant) brush and grasses. The dry forests of the hilly uplands support carnauba and babassu palms and such plants as the cactus, the rock rose, and the rhododendron. One unusual plant of the sertão region is the evergreen aveloz, which can grow to heights of 15 to 20 feet and is used as a hedgerow to mark field boundaries. Underground water in the region often is too saline for irrigation or drinking.

The lower São Francisco flows through a floodplain of fine silt soils, and tropical semi-deciduous forest thrives there. Most of the original vegetation that grew along the river, however, has been cleared for agriculture.

Animals are not abundant in the São Francisco basin. Among the mammals are various marsupials, rodents (including the large capybara), and skunks; a small wild cat called the gato de mata; the titi monkey, which lives in the more wooded areas; and the armadillo, which is ideally suited to the harsh sertão environment.

Birds include the partridgelike tinamous, notably the red-winged tinamou (Rhynchotus rufescens), as well as doves, parrots, the yellow finch, and the ubiquitous vulture. The drier areas of the basin have some smaller birds, such as hummingbirds and the sabia, a songbird of the thrush family. The birds of the São Francisco basin are greatly prized in Brazil as pets. Their numbers have been reduced, however, by the clearing of habitat for crops and pastures and by hunting.

The river's fish are an important food source. Among the major food species are robalo (a kind of snook), sardines, pocomó, and sarapó. In addition, the river mouth contains manatees (sea cows) and various species of sharks.

The São Francisco basin in general is inhabited by people of mixed Portuguese, Indian, and African descent. Most people in the coastal region, however, are of predominantly African ancestry, since that region was the main destination of the slave trade to Brazil.

The upper-middle basin is an agricultural region in which cotton, beans, rice, and corn (maize) are grown. The region also produces pineapples, potatoes, maté (tea), melons, sugarcane, coffee, castor and cottonseed oils, and rum. Its major urban centre is Pirapora, Minas Gerais.

The dry sertão is used largely for livestock grazing, mainly cattle, goats, sheep, and donkeys. Along the riverbanks vazante agriculture is practiced: during the rainy season, shallow waterbeds (vassantes) are enclosed by bars of river sediment and support the cultivation of cassava (manioc), corn, beans, and melons. Truck crops are grown on the riverbanks, and carnauba wax, caroa fibre, and rubber are collected. The major city is the market centre of Salvador, the capital of Bahia state. Most of the lower river valley is dry and suitable only for grazing. On the coastal lowlands, rice and sugarcane are grown.

The São Francisco basin contains deposits of agate, gold, iron, diamonds, opals, antimony, galena (the principal ore of lead), mercury, copper, arsenic, manganese, cobalt, and pyrites. There also are deposits of salt, sulfur, alum, marble, limestone, and clay. The river's hydroelectric (hydroelectric power) potential, however, is its most important resource. The main centres of power generation for northeastern Brazil are at the Paulo Afonso Falls and the dam impounding the Três Marias Reservoir. In addition, hydroelectric plants at dams on the upper and lower stretches of the river supply power to the coastal cities of Salvador, Aracaju, and Recife.

The river basin also is important as a source of irrigation (irrigation and drainage) water. The largest storage dam, near Petrolina and Juàzeiro, impounds the vast Sobradinho Reservoir. In addition to the Três Marias Reservoir, there is a large reservoir at Pedra d'Água, and there are plans for a reservoir on the Jaguaribe and a 300-mile-long irrigation canal to join the São Francisco at Petrolina to branches in eastern Pernambuco, Paraíba, and eastern Ceará states.

The river is navigable for small steamers for more than 1,000 miles from Pirapora, Minas Gerais, to Petrolina and Juàzeiro. Sandbars at the river's mouth prevent the entry of deep-draft ocean vessels. There is a railway bridge across the river at Pirapora, and another bridge connects the cities of Petrolina and Juàzeiro. Although river transport is slow and difficult, the São Francisco is an important link between the mining districts of Minas Gerais and roads that radiate north and east from Juàzeiro.

The earliest European forays beyond the coast and into the São Francisco basin consisted of slave raids on the Indian population. Other than some scattered settlement for cattle ranching, little attention was given to the interior until the 19th century. Considerable scientific study was carried out in northeastern Brazil following the malaria epidemic of 1938, and the disease was eradicated from the region by 1940. Modern research has included groundwater inventories, aerial photographic and radar surveys of the basin, and exploration for economically exploitable minerals. In addition, early Indian settlements have been the focus of archaeological excavations, and the region's plants have been studied for their possible pharmaceutical value.