In the build-up to the First Civil War, he was appointed governor of Hull (January 1642), where the supplies raised to fight the Scots were stored, but the garrison prevented him taking up the post, and he returned to Charles at York. Once the war began, he was given command in the north (June), and was sent north to secure Newcastle upon Tyne. Once again he raised a troop of his own soldiers, his 'whitecoats', who gained much fame later. He was called back to Yorkshire by the local cavaliers, who faced destruction at the hands of Lord Fairfax and his son Thomas Fairfax. Having increased the size of his army to 6,000 infantry and 2,000 cavalry, invading Yorkshire in November, and reaching York at the start of December. From York, he launched an attack on Lord Fairfax, who was then at Tadcaster, but was repulsed with the heavier losses (6 December). In the aftermath, Lord Fairfax retreated to Selby, while Newcastle sent detachments to occupy Pontefract castle, threatening communications between the Parliamentary garrison of Hull and their stronghold in west Yorkshire, and Newark, a key point on the River Trent, which remained in Royalist hands until the end of the war.
At the start of 1643, he returned to York, where on 7 March he was joined by Queen Henrietta Maria, newly arrived in England from the continent. With her was James King, later Lord Eythin, a professional soldier who became Newcastle's second in command. At this time he was also joined by George Goring, an able cavalry commander. At this time he was negotiating with Sir John Hotham, who was bitter at the way he had been made subordinate to the Fairfaxes, but at the start of June, just as they were about to surrender Hull to the Royalists, the Hothams were arrested. (They were later executed after the capture of Newcastle's letters after Marston Moor revealed the extent of their talks). The Queen having moved on, Newcastle was now free to concentrate on the Fairfaxes. At the battle of Adwalton Moor (30 June 1643), Newcastle with 10,000 men beat the Fairfaxes 4,000, and secured all of Yorkshire, at least for the moment. In the aftermath of the battle, Newcastle's troops even captured Thomas Fairfax's wife, but in a gesture typical of his attitude to war, she was sent to join Fairfax at Hull. Having won this victory, Newcastle then dawdled, and soon found himself responding to events. On 20 July Gainsborough fell to Parliament, and a relief force was defeated at the battle of Gainsborough (28 July 1643), but the arrival of Newcastle with his main army drove off the Parliamentary forces, who also surrendered Lincoln. Newcastle now made his greatest mistake. The Eastern Association lay at his feet, and a move against them would have severely damaged the Parliamentary cause. Instead, in a move typical of the Royalist armies, his men preferred to deal with Hull first, rather than leave their own region. The siege of Hull (2 September-11 October 1643) was doomed from the start - the garrison were secure behind a double line of defences, and retained control of the Humber, which allowed them to get supplies into the city, while Newcastle ignored royal orders to march on London.
1644 saw the situation in the north transformed by the entry of the Scots on the Parliamentary side. On 19 January they crossed the Tweed with an army 20,000 strong, Newcastle having failed to secure Berwick, one of the few properly fortified towns in England, which would have caused great problems for the Scots. Newcastle, with only 8,000 men, now had to race the Scots as well as the revived Fairfaxes. Despite this, Newcastle managed to delay the Scots, attacking their supply lines, and even attempting to provoke battle at Newcastle (23 March), but the Scots were still able to advance, reaching as close as two miles from Newcastle's headquarters at Durham on 8 April, while on 12 April he received news of the battle of Selby, where the garrison he had left in York had been defeated. The following day, he abandoned Durham and returned as fast as possible to York, to prepare for a siege. By the time the siege began (22 April), he and James King, Lord Eythin, had organised the supplies in York to allow them to withstand a lengthy siege. In the city he had 4,800 troops, initially facing 21,000 Parliamentary troops, soon swelled to 30,000. York was defended by a outer line of modern bastions and block-houses, and the inner line of the older medieval walls. Newcastle held both lines until 5-7 June, when a three day assault forced him behind the inner wars, much more vulnerable to damage.
While the fighting around York went one, Prince Rupert with a relief army was approaching. When news of his approach reached the Parliamentary commanders, they moved their army to Long Marston, where they expected to block Rupert's path, but he cut across two rivers to reach York. Newcastle's role in the build up to the Battle of Marston Moor (2 July 1644) was not creditable. Taking offence at the nature of Rupert's communications, he arrived five hours late and without his infantry, which only arrived later in the day. During the battle Newcastle played an active part, even killing three of the enemy himself while supporting an attack, but once it was clear the battle was lost, he and Eythin made their way back to north. His 'whitecoats' remained on the battlefield until the bitter end, fighting until almost wiped out. In the aftermath of the defeat, Newcastle decided to go into exile, saying
I will go to Holland. I will not endure the laughter of the Court.
This was a disaster for the Royalist cause in the north, as it triggered a wave of defections amongst less dedicated Royalists. His place of exile changed several times, before he settled in Antwerp (1648-60), where he lived in relative poverty until he managed to gain an allowance from the income of his old estates. He returned to London with Charles II (1660), but despite the huge amount of money he had spent in the Royalist cause, his full estates were never restored, and despite being created duke of Newcastle in 1665, he withdrew to his Welbeck estates