With both sides preparing for hostilities, Holles was appointed to the Committee of Safety on 4 July 1642, and helped organise the Dorset militia before returning to London to raise a regiment of infantry. In August, he marched to join the main Parliamentarian army assembling at Northampton and on 23 August took part in one of the first skirmishes of the war at Southam, before joining an unsuccessful attack on Sherborne Castle in early September. At Edgehill in October, his regiment helped prevent a Parliamentarian rout, before being largely destroyed just outside London at Brentford on 9 November.