Chester mattered to both sides for a reason that had nothing to do with its medieval walls or its Roman past. The city sat on the River Dee, within easy reach of the Irish Sea, and it was the principal English port for traffic to and from Ireland. King Charles needed Irish soldiers and Irish supplies, and Chester was the gate through which they passed. When the Civil War broke out in 1642, the city declared for the King. The Royalists strengthened the medieval walls and added a ring of earthwork defences extending out around the northern and eastern approaches. In March 1643 Parliament appointed Sir William Brereton, a Cheshire man, to command its forces in the county. Over the next year Brereton took most of Cheshire. Chester held out under Lord Byron, and the long war between the Roundheads outside the walls and the citizens inside began.

On 20 September 1644 Brereton advanced upon Chester and captured parts of the outworks. Byron rejected the summons to surrender, and a partial siege began. Brereton's force was too small for a complete blockade. Provisions and powder still trickled into the city in small quantities, and Royalist garrisons in the surrounding country sallied out to harass his lines. An assault in late October failed. The loose siege continued through the winter. In February 1645 Prince Maurice approached with a relief force, and Brereton lifted the siege; thirty days later Prince Rupert took twelve hundred seasoned troopers away with him, leaving Byron with only six hundred regular soldiers and the citizens themselves under arms. Brereton re-encircled the city. Three weeks later he was ordered to withdraw to the Mersey to face another Royalist threat, and the siege lapsed again through the spring and summer.

In early September 1645 the King's main army had been broken at Naseby. Charles withdrew to Raglan, then marched north with around 2,500 men hoping to rally Royalist support. On 20 September a New Model Army force under Colonel Michael Jones broke through the Royalist earthworks in Chester's eastern suburbs, burned the urban areas in front of the East Gate, and dragged artillery up to St John's Church to bombard the city walls. Charles reached Chester from the west on 23 September with his lifeguards. Sir Marmaduke Langdale took three thousand Royalist horse north from Holt at dawn the following day, hoping to catch the besiegers between his cavalry and an enlarged garrison. The Parliamentarian commander Sydnam Poyntz had ridden through the night to intercept him. The two cavalry forces met at Rowton Moor, southeast of the city. The fight lasted hours without an advantage on either side until Parliamentarian reinforcements arrived from Chester at two in the afternoon. The Royalists were routed. Among the killed was the King's own cousin, Lord Bernard Stewart. Charles is said to have watched the disaster from the Phoenix Tower on the city walls.

On 25 September Charles slipped away west with five hundred horse to Denbigh, leaving Byron and the garrison behind. The Parliamentarians re-encircled the city and resumed bombardment. By the next day they had opened a breach at Newgate. An assault on 8 October failed, and Brereton settled in to starve the city out. The siege continued for three months. The Royalists in the garrison refused to surrender or even consider terms. The food ran out. Many of the inhabitants died of starvation, not soldiers, not combatants, but the families who happened to live inside the walls and could not leave. The contemporary records do not give the total. They simply say many died. In January 1646 William Ince, the Mayor, persuaded Byron to negotiate. Talks opened on 20 January and concluded on 1 February. On 3 February the Parliamentarians marched in.

The city Brereton occupied that winter was a wrecked one. The siege had destroyed dwellings, mansions, barns, work-houses, dairy-houses, halls, and chapels. Many churches were severely damaged. The city's funds were exhausted. The damage is still visible in the city walls today. Paler sandstone fills the breach in the wall that Jones's guns opened in September 1645. Musket-ball marks pock Bonewaldesthorne's Tower. Cannonball damage still scars Barnaby's Tower. The Phoenix Tower, from which the King is said to have watched Rowton Heath, still stands. A plaque on the Goblin Tower records the repairs after the war. Skeletons were later found beneath Morgan's Mount when the Chester Canal was dug a century later, evidence of where the Royalist Captain Morgan placed his guns and where men died defending the walls. The citizens who starved have no monument. The walls remember them in silence.