Guilford was the eldest son of Frederick North, 2nd Earl of Guilford (commonly known as Lord North) who served as Prime Minister of Great Britain from 1770 to 1782, and his wife Anne (née Speke), Ranger of Bushy Park from 1771 to 1797.

[2] He was elected to the House of Commons for Harwich in 1778, a seat he held until 1784, and then represented Wootton Bassett from 1784 to 1790, Petersfield in 1790 and Banbury from 1790 to 1792.

Together, they were the parents of:[1] It was while courting his second wife that Guilford sustained a spinal injury in a fall from his horse and died from a lingering illness that resulted in April 1802, aged 44.

[3] On his death his junior title of Baron North fell into abeyance between his daughters while he was succeeded in the earldom by his younger brother, Francis.

Guilford's son-in-law, the Marquess of Bute, brought a petition to the House of Lords to resolve the partition of the late Earl's estate between his widow and his daughters.