It rises in the Serra da Canastra in western Minas Gerais and heads north, running behind the coastal ranges through Minas and Bahia before swinging east to become the border between Bahia on one bank and Pernambuco and Alagoas on the other, then finally between Alagoas and Sergipe on its way to the sea. That is 2,914 kilometres — the longest river contained entirely within Brazil, and the fourth longest in South America. Its basin drains more than 640,000 square kilometres and takes in tributaries from Goiás and the Federal District as well as the five states the river itself touches. Water reaches it from 168 rivers and streams: ninety on the right bank, seventy-eight on the left.

The phrase Brazilians use is rio da integração nacional. The São Francisco crosses climate zones the way few rivers do, tying the wet Southeast to the semi-arid Northeast, and for a long stretch of its middle course it is the only reliable water in a landscape defined by drought. Towns along it are small and far apart; the hinterland is thinly settled and hard. The exceptions are Petrolina in Pernambuco and Juazeiro in Bahia, twin cities on opposite banks that grew prosperous on irrigated fruit — mangoes and table grapes pulled out of the sertão by pumping the river onto it.

The river was worked for a century by paddle-wheel steamers called gaiolas, cages, some of them Mississippi boats that had been old already during the American Civil War. Their prows carried carrancas — carved wooden figureheads, part gargoyle and part guardian, meant to frighten off the demons the river was believed to keep. The demons persisted in the stories; the boats did not. After the Sobradinho dam went in, its reservoir was large enough to raise short steep waves that made the crossing miserable, and upstream deforestation and irrigation cut the flow until sandbanks closed the middle channel to anything large. Hulls of the old gaiolas still sit at Pirapora. One boat, the Benjamim Guimarães, was still running tourist trips from there as of 2009.

More than 200 fish species are known from the basin and more are expected, especially from the poorly surveyed upper river. About sixty-four percent of them are found nowhere else. The endemics include Lophiosilurus alexandri, a flattened catfish that lies on the bottom looking like part of it; Orthospinus franciscensis, a characin and the only member of its genus; and Salminus franciscanus, a relative of the golden dorado. More than forty species of annual killifish live in the basin's seasonal pools, mostly in the genera Cynolebias and Hypsolebias, hatching, breeding and dying inside a single wet season while their eggs wait out the dry one in the mud. Roughly one species in ten is threatened.

Below Paulo Afonso the river drops into a gorge and stays there most of the way to Penedo, walls of rock on both sides — the finest scenery on the whole course, and the stretch between the Paulo Afonso complex and the Xingó dam is protected as the 26,736-hectare Rio São Francisco Natural Monument. Upstream, the Sobradinho reservoir covers 4,214 square kilometres, among the largest artificial lakes on Earth. Then in 2005 the government proposed diverting water from an intake at Cabrobó to serve semi-arid parts of Ceará, Pernambuco, Paraíba and Rio Grande do Norte. Supporters call it overdue relief for people who have never had a dependable supply. Opponents argue the benefit flows mostly to large landholders while the ecological cost falls on the river. Both arguments are still going.