In April 1645, he is listed as Lieutenant Colonel of a cavalry regiment in the forces led by Sir William Brereton, Parliamentarian commander in the North Midlands.

Fairfax combined with Brereton on a number of occasions, including the Battle of Nantwich in January 1644, and Twisleton's unit may have remained in the area to support the Siege of Chester.

[3] The Battle of Naseby in June 1645 turned the war decisively in favour of Parliament, while the surrender of Montgomery Castle shortly afterwards cemented their control of the county.

[10] When the Second English Civil War began in April 1648, John Owen, former Royalist Governor of Conwy, raised a small force in Carnarvonshire.

On 3 June, he laid siege to Caernarfon Castle; Twisleton marched to its relief, and two days later Owen intercepted him near Y Dalar Hir on the shore of the Menai Straits.

[11] Combined with an earlier victory at St Fagans in May, this ended serious Royalist resistance in Wales, although Anglesey was not finally subdued until October.

[13] He focused instead on establishing his position in Denbigh, marrying Mary Glynne, an heiress whose father was Lord Chief Justice from 1655 to 1660, while her brother William was Member of Parliament for Caernarfon in 1659.