In 1959, excavators digging beneath the Minster and its churchyard uncovered the remains of an opulent Roman villa, one of only three of its type known from the territories of the Corieltauvi tribe. Part of a mural from the dig is now displayed inside the Minster itself. The Venerable Bede records a mass baptism in the flood of the Trent near a place called Tiovulginacester, conducted by Paulinus in 627 with King Edwin of Northumbria looking on. Scholars argue about whether Tiovulginacester was Southwell, but Paulinus certainly came through, and a Saxon church was probably built here soon after. The relics of Eadburh, an abbess of Repton who died around AD 700, were translated to Southwell and revered there throughout the Middle Ages; a Pilgrims Guide written around the year 1000 notes simply that there resteth St Eadburh in the Minster of Southwell near the water called the Trent. The town's first dated reference comes from 956, when King Eadwig granted the land to Oskytel, Archbishop of York.

On Church Street stands the Saracen's Head, a coaching inn built in 1463 on land that had been gifted to John and Margaret Fysher in 1396 by Archbishop Thomas Arundel. It became one of the most consequential buildings in seventeenth-century English history. In May 1646, with the third siege of Newark dragging into its sixth month, Charles I rode quietly into Southwell in disguise and spent what turned out to be his last night as a free man at the inn, then called the King's Head. The following morning he surrendered to the Scottish Presbyterian army stationed at nearby Kelham. Cromwell's troops subsequently descended on the town, stabled their horses in the Archbishop's Palace next to the Minster, broke open the graves of medieval clergy for the lead in their coffins, and reduced the palace to the ruined Great Hall it remains today. Iron rings driven into the palace walls to tether the horses were still visible in 1793. The Saracen's Head is still a working hotel and pub. The bedroom where Charles I spent his last free night is the room above the front entrance.

In 1803 Lord Byron, then fifteen and the new sixth Baron Byron of Rochdale, spent his school holidays with his mother in Burgage Manor, rented because Newstead Abbey was unaffordably dilapidated. He wrote a few poems here, including the splendidly tasteless Epitaph of John Adams, of Southwell - A Carrier, who Died of Drunkenness. Around the same time, on Church Street, a young woman called Mary Ann Brailsford planted apple pips from an unidentified fruit. By 1809 one of those pips had grown into a tree bearing a hard, intensely acidic apple that broke down beautifully when cooked. The seventeen-year-old local nurseryman Henry Merryweather, who tasted the apples and saw their potential, asked permission from the cottage's later owner Matthew Bramley to graft from the original tree. Merryweather named the apple after the man who owned the garden, not after the woman who grew it, and the Bramley became the standard British cooking apple. The original tree still stands in Bramley Tree Cottage, propped up and elderly but still producing fruit. A stained-glass window in the Minster, installed in 2009, marks the apple's bicentenary.

On the edge of town, the Southwell Workhouse opened in 1824 as a prototype of the punitive parish-by-parish system that the New Poor Law of 1834 would impose across England. It was designed by architect William Adams Nicholson working alongside Rev. John Thomas Becher, a local cleric and social reformer who believed in the strict separation of the deserving from the undeserving poor. The architecture deliberately segregated men from women, the elderly from the able-bodied, and the well-conducted from the disorderly. The National Trust has owned the building since 1997 and presents it largely as the inmates would have seen it in the 1840s. The bleached limewash walls, the silent corridors, the bare yards, and the audio recreations of children separated from their mothers add up to the most uncomfortable historic-house experience in the Midlands, which is precisely the point. Southwell itself, by contrast, escaped most of the suffering that produced the workhouse. The town is twinned with Sées in France, Sarzana in Italy, and Český Brod in the Czech Republic, hosts the annual Southwell Music Festival each August in the Minster, and remains the kind of place where wealthier Nottinghamians like to live.