Wisbech sits at the intersection of two A roads and the only tidal river in Cambridgeshire — the River Nene — which still connects the town to the sea. The name may derive from the River Wissey, which once ran to Wisbech, meaning "the valley of the river Wissey." In the Iron Age the area lay within the territory of the Icenian tribe; Icenian coins have been found here. The town appears in the Domesday Book as Wisbeach; by that point, it already had a castle and around 300 to 350 people. The great flood of 12 November 1236 swept away much of the town, drowned hundreds, and destroyed the castle. Wisbech rebuilt itself each time. The town's position at the edge of navigable water made it important, and importance has a way of surviving disasters.

Wisbech has over 250 listed buildings and monuments, concentrated along the river and known as The Brinks — the North Brink and South Brink that run along each bank of the Nene. The North Brink is widely considered one of the finest Georgian streetscapes in England. Peckover House (1722), now owned by the National Trust, anchors one end; Elgood's Brewery (1795) marks another point along the same stretch. The Crescent, a circus of terraced houses surrounding the site of Wisbech Castle, represents another phase of the same ambition. Much of this architecture was built on the prosperity generated by the draining of the Fens — farmland reclaimed from marsh, funneled through a port that in the early 19th century handled an annual average of 40,000 tons of goods: coal, corn, timber, wine. The buildings that prosperity built remain. The prosperity itself has been more variable.

Wisbech has generated an unusual number of people who changed things. Thomas Clarkson spent his life gathering evidence against the slave trade and building the coalition that eventually ended it. His younger brother Lieutenant John Clarkson RN organized the voluntary migration of formerly enslaved people to Sierra Leone after the American War of Independence. Octavia Hill helped found the National Trust and pioneered social housing reform. Miranda Hill, her sister, founded the Kyrle Society, a precursor to the National Trust. Priscilla Hannah Peckover founded the Wisbech Local Peace Association, which grew to 6,000 members. Harry Kroto — born Heinrich Fritz Kroto, son of a Jewish refugee from Germany — attended Wisbech Grammar School before going on to discover fullerenes at Rice University in Houston, for which he shared the 1996 Nobel Prize in Chemistry. William Godwin was born here in 1756; his daughter became Mary Shelley. The Reverend W. Awdry lived nearby and drew on the small steam trams of the Wisbech and Upwell line for the character of Toby the Tram Engine.

Wisbech's population shifted dramatically in the early 21st century with Lithuania's accession to the European Union in 2004. By 2014, an estimated 6,000 Lithuanians were living in a town of about 30,000 people, drawn by agricultural and food processing employment in the surrounding Fens. The community has established its own cultural calendar — celebrating Užgavėnės, the Lithuanian pre-Lenten festival, in collaboration with local institutions including the Wisbech and Fenland Museum. The town has always been shaped by people moving through or settling near its river: medieval fishermen, Tudor merchants, Victorian fruit pickers who arrived by special rail fares, and now families who built new lives in the flatlands of East Anglia. The Nene still runs to the sea. The town still sits beside it.