The main threat to his position was the Royalist army being raised by Lord Herbert in Wales. At the start of March 1643, this army was threatening Gloucester. Waller marched from Bristol to Malmesbury, which he captured easily, crossed the Severn on a bridge of boats downstream of Gloucester, and after a quick march through the Forest of Dean surprised Lord Herbert's troops at Higham (24 March 1643), where the newly raised Welsh infantry quickly surrendered. After his victory, Waller moved into Monmouthshire, capturing and garrisoning Monmouth and Chepstow, with the intention of obstructing Royalist recruiting. Herbert had raised another force from garrisons, and was threatening Waller from the west, while Prince Maurice, who had been sent to help Herbert, crossed the Severn north of Gloucester, and attempted to block Waller's route back to the city. Waller dealt with this by sending his slow moving infantry, guns and baggage back across to the south bank of the Severn, and then breaking through Maurice's lines with his cavalry. Reinforced by Massey with some of the garrison of Gloucester, he was still outnumbered by Prince Maurice, and on 13 April was defeated at Ripple Field, his first defeat of the war. However, Maurice was soon withdrawn from the area, and Waller recovered, capturing Hereford on 25 April, but the increasing threat posed by the Royalists of Cornwall commanded by Sir Ralph Hopton was soon to engage all of his attention.
The Royalists had now put together a sizeable force, some 5,500 strong and with 14-16 cannon, formed by the merger of Hopton's victorious Cornish force, and a force under Prince Maurice, once again returned to the west. Command appears to have been held by Hopton under the nominal leadership of the Marquis of Hertford. This force secured Somerset, while Waller, with a similar sized force, waited at Bath. When the Royalists advanced towards Bath, they found Waller strongly positioned on top of Lansdown Hill. The resulting Battle of Lansdown (5 July 1643) was a heavily fought draw, with the Royalists only narrowly avoiding disaster, but Waller was forced to abandon the field, although the Royalists morale suffered most after the death of Sir Bevil Grenvile, and a serious injury to Hopton after the battle, and it was the Royalists who eventually retreated, with Waller hassling them all the way back to Devizes. The tables were turned at the battle of Roundway Down (13 July 1643), when Waller was defeated by a combination of the forces already in Devizes and a relief force that marched at speed from Oxford. Waller's army was almost totally destroyed, losing 600 dead and 800 captives, while very few of the survivors ever fought again.
After Roundway Down a rift developed between Waller and Essex. Waller reached London on 25 July, and was received as a conquering hero, while Essex was blamed for allowing the Royalist relief force to leave Oxford unmolested. Waller was now given a new command, commanding the forces of a new South-Eastern Association (Kent, Surrey, Sussex and Hampshire), where he once again found himself facing Hopton. His first move, in early November, was to attempt to besiege Basing House, but within days he was forced to abandon this attempt by a mutiny of the London Trained Bands, unwilling to serve away from London unless in an emergency. Hopton made an attempt to force battle at Farnham, but Waller wisely refused, and Hopton went into winter quarters. Now Waller moved. He defeated one quarter of Hopton's army at Alton (13 December 1643), then captured Arundel Castle on 6 January, where he took 1,000 prisoners, 500 of whom changed sides. When the two armies finally clashed (Battle of Cheriton, 29 March 1644, also known as Alresford), Waller's force was victorious, although his leadership was not without flaws. Despite that, this was the first major Parliamentary victory, and Waller's reputation was much enhanced.
Emboldened by this, the Parliamentarians advanced on Oxford. For a brief period, Essex and Waller co-operated, but this did not last, and after Charles gave them the slip and marched his army to Worcester, they decided to split, leaving Waller alone to chase the king. Even so, when the two sides came to battle, (Cropredy Bridge, 29 June 1644), Waller slightly outnumbered Charles (9,000 to 8,500). Despite that, Waller still came off the worst in the battle, losing much of his artillery. Once again, Waller returned to London in July without an army.
His next significant activity was at the 2nd Battle of Newbury (27 October 1644). Once again, Waller had been granted an independent command, which had made a half-hearted attempt to besiege Oxford, which gave his strong voice on the committee that commanded the Parliamentary armies at Newbury, second behind Manchester as Essex was too ill to take part. It was probably Waller who proposed the Parliamentary plan for a long flanking march, intended to attack Charles from front and back, and he commanded the flanking force, containing his own force, as well as Essex's army and Cromwell's cavalry. In the event, the plan failed when Manchester failed to time his attack to match Waller's, allowing Charles to escape with most of his army.
The failure at Newbury had a long term impact on Waller. The inquest into the battle led to the formation of the New Model Army, and the Self Denying Ordinance, which ended Waller's career as a general, and saw him return to Parliament. Once there he became a leader of the Presbyterian faction in Parliament, which soon came into conflict with the largely independent New Model Army, going as far as levying troops against them in 1647, after which he temporarily withdrew to France. Returning to England in 1648, he was a moderate voice urging Parliament to make terms with Charles, and for three years was a prisoner of the army. Ironically, he now became an Royalist. He was temporarily arrested by Cromwell in 1658, but released, and in 1659 actually plotted for a Royalist revolt, ending up a prisoner in the Tower. When the Long Parliament was restored in full in 1660, Waller regained his place, even gaining an appointment on the Council of State, where he urged the restoration of Charles II. Despite that, and his role in the Convention Parliament (1660) as MP for Westminster, he was not rewarded after the Restoration. Waller is a good example of the changes of fortune that affected many Parliamentarians once the war had been won.