The genealogy of the Mercian kings claims descent from Wóden through Offa, king of all the Angles, but Penda and because of him Mercia rose from obscurity to great power during his lifetime. He may or may not have become king in 626. His first recorded battle - as king or as an independent warlord or a rival claimant to the Mercian throne - was at Cirencester in 628, against the West Saxons under their kings Cynegils and Cwichelm. After the battle, says the Anglo-Saxon Chronicle, Penda and the West Saxons "came to an agreement." Possibly this means they ceded to him Cirencester and the areas along the lower River Severn. These lands, to the southwest of Mercia, had apparently been taken by the West Saxons from the British in 577.

At some point in the late 620s or early 630s, Cadwallon ap Cadfan, King of Gwynedd, became involved in a war with Edwin of Northumbria, the most powerful king in Britain at the time. Cadwallon apparently was initially unsuccessful, but allied with Penda he defeated the Northumbrians in October 633 at the Battle of Hatfield Chase. Edwin was killed in the battle, and one of his sons, Eadfriþ, was captured by Penda, who eventually had him killed. Cadwallon went on to kill King Osric of Deira but was then defeated and killed by Oswald of Bernicia at the Battle of Heavenfield, about a year after Hatfield Chase; there is no record of Penda being there on either occasion. Oswald, who had succeeded Edwin as ruler of Northumbria, and Penda appear to have kept a wary eye on each other for a number of years, but at some time after 635, Penda attacked the East Angles and defeated them, killing both their king Egric and the former king Sigeberht, who after bringing about the conversion of his kingdom to Xianity had become even more saintly, retiring to a monastery and renouncing all violence. He had been dragged onto the battlefield to inspire the soldiers but would not raise a weapon and Penda cut him down in prayer.

Whether this victory scared or revolted Oswald or whether he was trying to take advantage of dynastic strife between Penda and his brother, Eowa, Oswald evidently invaded Mercia to challenge Penda, and duly met death at his hands on August 5, 642 in Oswestry, at the Battle of Maserfield. The location is near Welsh territory, and Welsh sources suggest Penda was again allied with Welshmen, this time the men of Powys, possibly including Cynddylan ap Cyndrwyn, who is said to have always been eager to aid "the son of Pyb" (Penda's father was Pybba). Eowa was also killed, fighting on which side is not recorded. Bede tells us that Penda had Oswald's body dismembered and his head, hands and arms placed on stakes; Oswald later came to be one of several Anglo-Saxon royal saints, known as "Oswald, King and Martyr."

Penda's victory at Maserfield made him the most powerful king in England, fractured Northumbria back into separate Deiran and Bernician kingdoms, and made the new West Saxon king, Cenwealh - he who had declined to be baptized with his father Cynegils - feel bold enough to marry Penda's sister. Unfortunately he then felt bold enough to "repudiate" her and take a different wife, whereupon Penda drove him into exile in East Anglia in 645 (where he did get baptized).

In 654 Penda slew Cenwealh's protector, the East Anglian king Anna, at Bulcamp near Blythburgh in Suffolk. He was succeeded by a brother, Aeþelhere; since Aeþelher participated in Penda's invasion of Bernicia in 655, he may have been Penda's choice; or he may have just seen the writing on the wall. Penda established his son Peada as ruler of the Middle Angles, a kingdom that he likely created out of a group of small peoples. He seems to have established another vassal kingdom on the Welsh marches. He was adept at consolidating power.

There was also of course a religious dimension to Penda's wars. In the years after Maserfield, he destructively waged war against Oswiu of Bernicia on his own territory. At one point prior to the death of Bishop Aidan in 651, Bede says that Penda "cruelly ravaged the country of the Northumbrians far and near" and besieged the royal Bernician stronghold of Bamburgh. When the Mercians were unable to capture it - "not being able to enter it by force, or by a long siege" - Bede reports that they attempted to set the city ablaze, but that it was saved by a sacred wind supposedly sent in response to a plea from the saintly Aidan: "Behold, Lord, how great mischief Penda does!" The wind is said to have blown the fire back towards the Mercians, deterring them from further attempts to capture the city. At another point, some years after Aidan's death, Bede reports that Penda led an army in devastating the area where Aidan died - he "destroyed all he could with fire and sword" - but that when the Mercians burned down the church where Aidan had died, the post against which he had been leaning at the time of his death remained miraculously undamaged. Oswiu seems to have avoided battle due to a feeling of weakness relative to Penda. It probably seemed as if Penda was not only a military genius, but had greater power from his gods than Oswiu dared expect from his. He tried to make some sort of peace: Penda's daughter Cyneburh married Oswiu's son Alhfriþ, and Penda's son Peada married Oswiu's daughter Alhflaed. According to Bede, the latter marriage was on condition that Peada accept Xianity, which he did, and proselytizing began among the Middle Angles. Bede says Penda did not impede this, but saved his anger for hypocrites: "Nor did King Penda obstruct the preaching of the word among his people, the Mercians, if any were willing to hear it; but, on the contrary, he hated and despised those whom he perceived not to perform the works of faith, when they had once received the faith, saying, 'They were contemptible and wretched who did not obey their God, in whom they believed.'"

In 655, Penda invaded Bernicia with a large army, with thirty royal or noble commanders including rulers such as Cadafael ap Cynfeddw of Gwynedd and Aeþelhere of East Anglia. Penda also enjoyed the support of Æþelwald, the king of Deira and the successor of Oswine, who had been murdered on Oswiu's orders in 651; Bede says Æþelwald acted as Penda's guide during his invasion. Perhaps the objective was to prevent the reunification of Northumbria; perhaps it was to finally break Bernicia and install Æþelwald as a vassal king. The army besieged Oswiu at Iudeu, probably Stirling, in the north of Oswiu's kingdom. Oswiu offered treasure, which Penda either distributed among his British allies or simply rejected. Additionally, according to Bede, Oswiu's son Ecgfriþ was being held hostage "at the court of Queen Cynwise, in the province of the Mercians." Apparently Penda's forces then moved back south, perhaps homeward bound, but for whatever reason, possibly an ambush by Oswiu at a strategic point (the river was swollen by heavy rain), on November 15 a great battle was fought near the River Winwæd in Elmet. Penda's forces, although much greater than Oswiu's, were also weakened by desertions. Cadafael of Gwynedd had slunk away in the night with his army (earning him the name Cadomedd, or "battle-shirker") and when battle was joined, Æþelwald of Deira withdrew and "awaited the outcome from a place of safety." Penda may have been heading home because his army was already falling apart; or Æþelwald may have led him into a trap; Penda had killed his father Oswald and dismembered his body. The outcome was defeat for the Mercians and death for Penda and the East Anglian king Æþelhere. Bede says that Penda's "thirty commanders, and those who had come to his assistance were put to flight, and almost all of them slain," and that more drowned while fleeing than were killed in the actual battle. He also says that Penda's head was cut off.

With the defeat at the Winwæd, Oswiu came to briefly dominate Mercia, permitting Penda's son Peada to rule its southern portion. Two of Penda's other sons, Wulfhere and Æthelred, later ruled Mercia in succession after the overthrow of Northumbrian control in the late 650s. The period of rule by Penda's descendants came to an end with his grandson Ceolred's death in 716, after which power passed to descendants of Eowa for most of the remainder of the 8th century. Xianity was able to resume its march through England: the Mercians were converted, and all three of Penda's reigning sons were Xian kings. His daughters Cyneburh and Cyneswiþ became saintly figures who according to some accounts retained their virginity through their marriages. There was purportedly even an infant grandson of Penda named Rumwold who lived a saintly three-day life of fervent preaching.