Throughout the Early Middle Ages, Powys was ruled by the Gwerthrynion dynasty, a family claiming descent jointly from the marriage of Vortigern and Princess Sevira, the daughter of Magnus Maximus. Archaeological evidence has shown that, unusually for the post-Roman period, Viroconium Cornoviorum survived as an urban centre well into the 6th century and thus could have been the Powys capital. The 9th-century Historia Brittonum records the town as Caer Guricon, one of his "28 British Towns" of Roman Britain. In the following centuries, the Powys eastern border was encroached upon by English settlers from the emerging Anglian territory of Mercia. This was a gradual process, and English control in the West Midlands was uncertain until the late 8th century.

In 549 the Plague of Justinian - an outbreak of a strain of bubonic plague - arrived in Britain, and Welsh communities were devastated, with villages and countryside alike depopulated. However, the English were less affected by this plague as they had far fewer trading contacts with the continent at this time. Faced with shrinking manpower and increasing Anglian encroachment, King Brochwel Ysgithrog may have moved the court from Caer Guricon to Pengwern, the exact site of which is unknown but may have been at Shrewsbury, traditionally associated with Pengwern, or the more defensible Din Gwrygon, the hill fort on The Wrekin.

In 616, the armies of Æthelfrith of Northumbria clashed with Powys. According to Geoffrey of Monmouth, the Northumbrian monarch's political rival, Edwin of Deira, was living in exile in Gwynedd around this time. Historians such as John Morris have suggested that Æthelfrith attempted to capture him, but presumably King Selyf ap Cynan of Powys denied access through Powys to Edwin in Gwynedd, and seeing an opportunity to further drive a wedge between the North Welsh and those of Rheged, Æthelfrith invaded Powys' northern lands. Æthelfrith forced a battle near Chester and defeated Selyf and his allies. At the commencement of the battle, Bede tells us that the pagan Æthelfrith slaughtered 1200 monks from the important monastery of Bangor-on-Dee in Maelor because, he said, "they fight against us, because they oppose us by their prayers". Selyf ap Cynan was also killed in the battle and may have been the first of the kings of Powys to be buried at the church dedicated to St. Tysilio, at Meifod, thence known as the Eglwys Tysilio and subsequently the dynasty's Royal mausoleum.

If King Cynddylan of Pengwern hailed from the royal Powys dynasty, then forces from Powys were also present at the Battle of Maes Cogwy in 642. Subsequent to this, the region around Pengwern was sacked, its royal family slaughtered and most of its lands were annexed by Mercia, some by Powys. These events were remembered in Welsh poems which told of the desolation of Princess Heledd (Canu Heledd) on hearing of the death of her brother (Marwnad Cynddylan).

Powys enjoyed a resurgence with successful campaigns against the English in 655, 705-707 and 722, wrote Davies. The court was moved to Mathrafal Castle in the valley of the river Vyrnwy by 717, possibly by king Elisedd ap Gwylog (d.c. 755). Elisedd's successes led King Æthelbald of Mercia to build Wat's ♥♥♥♥. This endeavour may have been with Elisedd's own agreement, however, for this boundary, extending north from the Severn valley to the Dee estuary, gave Oswestry (Welsh: Croesoswallt) to Powys. King Offa of Mercia seems to have continued this consultive initiative when he created a larger earth work, now known as Offa's ♥♥♥♥. Davies wrote of Cyril Fox's study of Offa's ♥♥♥♥:

In the planning of it, there was a degree of consultation with the kings of Powys and Gwent. On the Long Mountain near Trelystan, the ♥♥♥♥ veers to the east, leaving the fertile slops in the hands of the Welsh; near Rhiwabon, it was designed to ensure that Cadell ap Brochwel retained possession of the Fortress of Penygadden." And for Gwent Offa had the ♥♥♥♥ built "on the eastern crest of the gorge, clearly with the intention of recognizing that the river Wye and its traffic belonged to the kingdom of Gwent.

This new border moved Oswestry back to the English side of the new frontier, and Offa attacked Powys in 760 at Hereford, and again on 778, 784 and 796. Offa's ♥♥♥♥ largely remained the frontier between the Welsh and English, though the Welsh would recover by the 12th century the area between the Dee and the River Conwy, known then as the Perfeddwlad or "Midlands".