When Oswiu was about twenty, his father's killer, King Edwin, fell in battle against a combined force from Gwynedd and Mercia. The Prince's eldest half-brother, Enfrith - who had been hiding in Pictland - returned to Bernicia to claim his inheritance and was eagerly enthroned by their people. However, King Cadwallon of Gwynedd was in no mood to accept the rule of an Edwinian replacement and he too was soon slain.  In AD 634, Oswiu's other brother, Oswald, decided to try his luck instead. Having been lent an army by King Domnall Brecc of Dalriada, he was much better prepared for an encounter with the Welsh and the enemy was put to flight at the Battle of Heavenfield. Oswiu was almost certainly amongst the victorious Bernician warriors.

Having been in exile together, King Oswald much favoured his little brother, and Oswiu seems to have been a central character in the new monarch's expansionist policies. Only four years after snatching the throne, Oswald negotiated Oswiu's marriage to Princess Rhiainfelt, the last heiress of the once great Celtic kingdom of North Rheged. It seems probable that her father, King Rhoedd, died shortly afterward, leaving Oswiu as the first Saxon King of North Rheged, under the overlordship of his brother. The two continued to work closely together and Oswiu headed up the Northumbrian army which conquered Gododdin in AD 641. Unfortunately however, despite such successes, the Welsh and Mercians were not subdued and, the following year, they rose up with a great force. King Oswald marched south to meet them on their home ground, but was killed at the Battle of Oswestry.

Prince Aethelwald being rather young, his uncle, Oswiu, then took the throne. He may have been in Rheged at the time of the battle. However, Oswald had been the son of a Bernician father and a Deiran mother and was thus acceptable to both kingdoms of Northumbria; Oswiu was not. Deira rejected his rule and the late King Edwin's cousin, Oswin, managed to to re-establish his dynasty there. Since his wife was now dead, the new Bernician monarch tried to counter this move by sending for Edwin's daughter, Princess Enflaed, who was in exile in Kent. The two were married at Bamburgh in AD 643, but the Deirans still preferred their own King and armed conflicts followed. While Oswiu was busy fighting a civil war, the Mercians became strong once more. They rose up and wrested Elmet and Lindsey from his control. Under pressure, therefore, King Oswiu seems to have sought new allies and it was around this time (c.AD 650) that he spend some time in Ireland. He, apparently, had an affair with Princess Fin, the grandaughter of Colman Rimid Ui Neill, and their son, Prince Aeldfrith, was born soon afterward. 

In AD 651, Oswiu raised a great army for a one last push against Oswin of Deira. But the latter refused to engage him and hid out in Gilling. Completely frustrated, Oswiu had him assassinated: a shameful and unpopular move for which he was later obliged to turn the estate where the act took place into a religious establishment. It also failed to secure Deira for him. For the people  - possibly with Mercian help - raised to the throne, the late King Oswald's son, Prince Aethelwald. About this time, Oswiu married his eldest son, Prince Alcfrith, to King Penda of Mercia's daughter, Cuneburga, possibly in an attempt to stop further interference in Northumbrian affairs. The scheme did not work and, the following year, Penda, for a short while, was besieging Oswiu in the far north of his kingdom, at Bamburgh. In AD 655, he was back again with an even stronger force, swelled by his British allies in Wales. Oswiu's army was only a third the size and he, therefore, fled north to Stirling, his most northerly city. From the safety of the borders with Pictland - from where his nephew, King Talorcan I, had probably recognised his overlordship - Oswiu sent envoys to offer Penda offering bribes in return for his withdrawal. The Mercians took the cash and distributed it amongst their British allies. But the money had come from the oppressed Northern Britons of Gododdin, so Oswiu's British enemies viewed it as a restitution of their own property and ravaged Bernicia anyway. The two armies clashed at the Battle of Winwaed, but the forces from Gwynedd and Deira, unexpectedly withdrew. Penda's severely depleted force lost the battle and the man himself was killed.

At last, Oswiu was King of a united Northumbria, like his father and brother before him. He appointed his son, Alcfrith, as sub-king in Deira and allowed Penda's Christian son (and Oswiu's son-in-law), Peada,  to remain in Middle Anglia. The latter was murdered the following year, however, and Oswiu extended direct rule into Mercia, invaded Pengwern and killed King Cynddylan. The Mercians did not re-establish their independence - under Penda's youngest son, Wulfhere - until AD 658. Oswiu also tried to further extend his power northwards, by invading Pictland, in AD 663, a few years after the death of his Northumbrian-friendly nephew, King Talorcan I. However, there seems to be little support for Bede's claim that he made tributary the Dalriadan Scots. Meantime, troubles of a different kind were brewing for King Oswiu. About AD 660, his son, King Alcfrith of Deira, fell under the influence of Abbot Wilfred of Ripon and began to follow a religious policy completely independent of his father. He rejected the Celtic traditions of the Ionian Church and turned instead to the ways of Rome. Alcfrith was soon removed, but this religious controversy could not be ignore. The two parties could not agree on the correct form for calculating the Easter dates and the argument dominated Northern politics for the next four years, until, in AD 664, King Oswiu agreed to call the Synod of Whitby (Streoneshall) at the abbey in that town.

Oswiu had always been interested in matters of the church. He had been instrumental in the foundation of Melrose Abbey around AD 650 and it was during his reign that St. Cedd's mission had left Northumbria to re-establish the See of Essex. The King had even allowed his daughter, Aelfflaed, to become a nun at Hartlepool, under her second cousin, St. Hilda. The two had since moved on to Whitby, hence the King's choice of venue. The timing appears to have been due to the fact that, if the method for calculating the date of Easter was not standardised in Northumbria, the following year, the King and his Kentish wife would be celebrating the feast on different days! Bishop Colman of Lindisfarne & Abbot Wilfred of Ripon argued it out in front of the King. They appear to have agreed on little, until Colman was forced to admit that, as Wilfred insisted, St. Peter did indeed hold the keys to the kingdom of heaven. The impatient monarch then interjected that St. Peter's successor in Rome must therefore know when Easter should fall and abruptly closed the meeting with a knowing smile.

Colman resigned his see in protest soon afterward and Wilfred eventually succeeded him, but moved his Episcopal seat to York. His rule was short-lived however. Claiming there is no-one in Britain with the authority to consecrate him, he left for France and was enthroned by the Archbishop of Paris. Wilfred liked the Frankish Archiepiscopal court so much that he delayed his return and King Oswiu decided to appoint Abbot Chad of Lastingham as Bishop of York instead.

King Oswiu died in AD 670 of natural causes. He was buried in Whitby Abbey and succeeded by his sons, Egfrith as overlord of Northumbria and Aelfwin as sub-King of Deira.