Wilkes was born in London, the son of the distiller Israel Wilkes. He was educated at Leiden, a school in Hertford and also privately. In 1747 he married Mary Meade and so came into possession of an estate and income in Buckinghamshire. He soon gained the reputation as something of a rake and was a member of The Hellfire Club; and instigator of a prank that may have hastened its dissolution.
He stood for election to Parliament in 1754 in Berwick-on-Tweed but lost despite considerable efforts, including bribery. He became MP for Aylesbury in 1757 when, it was claimed, he spent over £6,000 during the campaign.
He was a supporter of William Pitt the Elder. When John Stuart, 3rd Earl of Bute came to power in 1762 Wilkes started a weekly publication, the North Briton, to attack him, using an anti-Scots tone. Bute resigned in 1763 but Wilkes was equally opposed to his successor, George Grenville. He was charged with seditious libel over attacks on the King's speech at the opening of Parliament in issue Number 45 of April 23, 1763. General warrants were issued for the arrest of the publishers and almost fifty people were arrested under the warrants. Wilkes was expelled from the House of Commons on January 19, 1764 and later arrested. He gained considerable popular support and was soon released and restored to his seat. The charges were judged unconstitutional and Wilkes began a case against his arresters for trespass.
Wilkes' opponents were quick to strike back; a manuscript of Wilkes was obtained and produced in the House of Lords where it was declared libel. Moves were soon underway to expel Wilkes again and this time he fled to Paris before his expulsion or trial. He was found guilty, in absentia, of obscene libel and of seditious libel and was declared an outlaw.
Wilkes hoped for a change in power to remove the charges, but exhausting his money and stock of goodwill on the continent he returned to England in 1768. He returned intending to stand as MP on an anti-government ticket and curiously warrants were not issued for his immediate arrest. He stood in London and lost but was quickly elected MP for Middlesex before surrendering to the King's Bench in April and on waiving his right to immunity he was sentenced to two years and fined £1,000. The charge of outlawry was overturned. When Wilkes was imprisoned on May 10 of that year for writing an article for The North Briton severely criticising King George III rioting broke out in London.
Wilkes expected an immediate pardon, which he did not receive and he was also expelled from Parliament in February 1769. He was re-elected by Middlesex in the same month only to be expelled and re-elected in March. In April, having been expelled and won the election again, Parliament declared his opponent the winner. In defiance Wilkes had himself elected an alderman of London in 1769, using his supporters group, the Society for the Defence of the Bill of Rights, to campaign for him. Wilkes eventually succeeded in convincing Parliament into expunging the resolution barring him from sitting.
On his release in 1770 he was made a sheriff in London and in 1774 he became Lord Mayor. Also in that year he was re-elected to Parliament, representing Middlesex. He was one of those opposed to war with the American colonies and he was also a supporter of the Association Movement and of religious tolerance. His key success was to protect the freedom of the press, removing the power of general warrants and also the ability of Parliament to punish political reports of debates.
He was well known for his verbal wit and his snappy responses to insults. For instance, one MP shouted to him "You Sir, will either die of the pox or the gallows!". Wilkes responded "That would depend on whether I embrace your mistress, or your principles."
His popularity fell from around 1780 as he became less radical. While he was comfortably re-elected for Middlesex that year and again in 1784, by 1790 he found so little support that he did not stand.