The Jacobite army had marched into England in November 1745 and made it as far as Derby, deeper than any of Charles's family had managed in over half a century of pretending to the throne. There they discovered they were almost alone. The English Jacobites had not risen. London was preparing its defenses. The army's officers convinced Charles to turn back on 6 December. They re-entered Carlisle on 19 December and continued north into Scotland the next morning, leaving a rearguard of roughly 400 men under Colonel John Hamilton to hold the city. The decision was almost unanimously condemned in his own war council. The defenders were given 46 pieces of artillery but very little ammunition; many of the English Manchester Regiment recruits had no arms at all.

The town garrison was commanded by Francis Towneley, a hot-tempered English Catholic who had served in the French army before joining the Jacobite cause. He led the Manchester Regiment, the only significant English unit Charles had managed to recruit. Of the 396 men who would eventually surrender, 114 were English from Towneley's regiment, 274 were Scots from Lowland units like Glenbucket's and Lord Ogilvie's, and 8 were French regulars. They were a mixed army of friends and strangers locked into a fort with crumbling defenses, watching the Duke of Cumberland's 5,000-strong army assemble outside their walls.

Cumberland arrived on 21 December with his advance guard, but the heavy guns he needed had been left behind at Lichfield during the chase north. For six days the siege was effectively a blockade while the artillery was hauled up. The first battery arrived on 25 December. On the 27th, more guns came from Whitehaven, escorted by 70 to 80 naval gunners under William Belford, who had served Cumberland in Flanders. On 28 December they opened fire. The bombardment continued, with one short pause for ammunition resupply, until the morning of the 30th. Hamilton offered to surrender. Towneley wanted to fight on; he believed they could hold out for better terms. He was overruled. The garrison capitulated on the afternoon of 30 December.

When regular armies surrendered to each other, the defeated were treated as prisoners of war. Cumberland refused this. As rebels, the Carlisle garrison was granted only their lives, subject to the king's pleasure, meaning trial rather than summary execution. It was a fine distinction. Most of the garrison were thrown into the castle dungeons without food or water for several days. In January they were transferred to York Castle. Twenty-seven men of the Manchester Regiment were executed, including nine officers hanged, drawn, and quartered in London on 30 July 1746. Towneley was among them; the court rejected his claim that he was still a French officer. Hamilton was executed on 28 November along with several others. Of 3,471 Jacobite prisoners indicted for treason after the rising, 93 were put to death, including 40 recaptured British army deserters. Thirty-three of the executions were carried out at Harraby Hill outside Carlisle in October and November 1746, almost all of them men from the garrison Charles had abandoned. Six hundred and fifty died awaiting trial. Nine hundred were pardoned. The rest were transported, most to the West Indies as forced labor. The Act of Indemnity in 1747 finally cleared the remaining prisoners, among them Flora MacDonald.