Guaire appears to have succeeded his father as king of the Ui Fiachrach Aidhne in 622. In 629 was fought the Battle of Carn Feradaig (Carhernarry, County Limerick.) where he suffered a defeat at the hands of the Munster king Faílbe Flann mac Áedo Duib (d. 639). His ally Conall mac Máele Dúib of the Ui Maine was slain. According to Keating, Guaire's reason for this campaign was to recover the Thomond region from Munster. Prof. Byrne believes that this defeat marked the true expansion of the Déisi Tuisceart into Thomond. He also states that this defeat may have paved the way for Rogallach mac Uatach (d. 649) in acquiring the overlordship of Connacht.
The next event recorded of Guaire in the annals is the Battle of Carn Conaill (in his home territory near Gort) in 649. In this battle he was put to flight by the high-king Diarmait mac Áedo Sláine (d. 665) of Brega. Diarmait was the aggressor in this war and the saga Cath Cairnd Chonaill gives much detail of this affair. Diarmait won the support of the monastery of Clonmacnoise and refused the request of Cummian(Cumméne Fota) (d. 662), the abbot of Clonfert, for a truce; who had been sent by Guaire to ask for one. Also Caimmín abbot of Inis Celtra put on curse on Guaire before the battle. However, Guaire was able to turn his defeat into a moral victory when upon submitting to Diarmait he outdid the high-king with his generosity to the poor. Diarmait granted him a peace treaty and friendship.
Also according to the saga, the following Munster allies of Guaire were slain in this battle: the king of Munster Cúán mac Amalgado (d. 641) (called Cúán mac Éndai in the saga); Cúán mac Conaill, king of the Uí Fidgenti; and Tolomnach, king of the Uí Liatháin. Byrne believes this is not probable however; based on Cúán mac Amalgado's death date in the annals and on the improbability of the Uí Liathain being involved in a conflict far from their territory in South Munster.. The Annals of Ulster and Annals of Innisfallen do not mention the Munster connection but the saga tradition is preserved in the Annals of Tigernach. Relations with the Ui Fidgenti are shown by the poem The Lament of Créide, a poem written about his daughter's lament for a prince of the Ui Fidgenti.
Anecdotes are told about his relations with such saints as Cumméne Fota of Clonfert, Caimmín of Inis Celtra, and Colmán mac Duach (Colman MacDuagh) of Kilmacduagh. He also was associated with the church at Tuam Gréine (Tomgraney) and was ancestor of two 8th century abbots there. He seems to have patronized the expansion of West Munster saints up the Shannon. For this reason, Byrne believes his influence must have extended into parts of Munster including overlordship of Corcomruad and Corco Baiscind tribes in Thomond and actual holdings in the later territory of Dál gCais. In the saga Scéla Cano meic Gartnáin (The Story of Cano mac Gartnain) the exiled prince of Dalriada comes to live at his court for a while where Guaire's daughter Créide falls in love with him. Creide however was married to Marcán mac Tommáin (died 653) the king of the Ui Maine.
Guaire is listed after his brother Loingsech mac Colmáin (d. 655) in the king lists. It is possible that his defeat at Carn Conaill caused a temporary abdication and entering of a religious life.. Upon Loingsech's death in 655, Guaire then became over-king of Connacht ruling until his death in 663. He was buried at Clonmacnoise.