[1] His father was the youngest son of Charles Spencer, 3rd Earl of Sunderland, the First Lord of the Treasury and Lord President of the Council under George I, and his second wife, Lady Anne Churchill (third daughter of the 1st Duke of Marlborough),[2] who served as Lady of the Bedchamber to Queen Anne.

[4] Spencer was the principal beneficiary under the will of his great-grandmother Sarah, Duchess of Marlborough who stipulated, however, that should he at any time accept "from any King or Queen of these realms any pension, or any office or employment, civil or military" (except the Rangership of Windsor Great or Little Park), the estate would pass to the next heir "as if the same John Spencer were actually dead.

In March 1756 Spencer, standing on the Whig interest, but lost in the exceedingly expensive by-election at Bristol where Jarrit Smyth was elected.

On 27 November 1760, Spencer wrote to the Duke of Newcastle, the Prime Minister of Great Britain, stating:[5] "As I am the representative of the Sunderland family, and as my particular circumstances are such (from the Duchess of Marlborough's will) that I cannot receive any favour from the King except a title, I should hope that if his Majesty thinks me worthy of a peerage he will not confer upon me a less dignity than that of a viscount...

[5] Therefore, he continued canvassing St Albans but toward the end of February 1761, he nominated Viscount Nuneham in his place, likely after being informed of his impending creation.

On his return they recognised their love had persisted, and shortly after his birthday they married in a secret ceremony on 20 December 1755 at Althorp, the Spencer family seat in Northamptonshire.

Intended to be worthy of Spencer's large collection of antiquities, the lavish residence took seven years and £50,000 to build.