George was born on 21 October 1449 in Dublin at a time when his father, the Duke of York, had begun to challenge Henry VI for the crown. His godfather was James FitzGerald, 6th Earl of Desmond. He was the third of the four sons of Richard and Cecily who survived to adulthood. His father died in 1460. In 1461 his elder brother, Edward, became King of England as Edward IV. In that year George was made Duke of Clarence and invested as a Knight of the Garter, and in 1462 Clarence received the Honour of Richmond, a lifetime grant, but without the peerage title of Earl of Richmond. Despite his youth, he was appointed as Lord Lieutenant of Ireland in the same year.
Richard Neville, Earl of Warwick
Having been mentioned as a possible husband for Mary, daughter of Charles the Bold, Duke of Burgundy, Clarence came under the influence of his first cousin Richard Neville, Earl of Warwick, and in July 1469 was married in Église Notre-Dame de Calais to the earl's elder daughter Isabel Neville.
Clarence had actively supported his elder brother's claim to the throne, but when his father-in-law (known as "the Kingmaker") deserted Edward IV to ally with Margaret of Anjou, consort of the deposed King Henry, Clarence supported him and was deprived of his office as Lord Lieutenant. Clarence joined Warwick in France, taking his pregnant wife. She gave birth to their first child, a girl, on 16 April 1470, in a ship off Calais. The child died shortly afterwards. Henry VI rewarded Clarence by making him next in line to the throne after his own son, justifying the exclusion of Edward IV either by attainder for his treason against Henry VI or on the grounds of his alleged illegitimacy.
After a short time, Clarence realized that his loyalty to his father-in-law was misplaced: Warwick had his younger daughter, Anne Neville, Clarence's sister-in-law, marry Henry VI's son in December 1470. This demonstrated that his father-in-law was less interested in making him king than in serving his own interests and, since it now seemed unlikely that Warwick would replace Edward IV with Clarence, Clarence was secretly reconciled with Edward.
Warwick's efforts to keep Henry VI on the throne ultimately failed and Warwick was killed in battle of Barnet April 1471. The re-instated King Edward IV restored his brother Clarence to royal favour by making him Great Chamberlain of England. As his father-in-law had died, Clarence became jure uxoris Earl of Warwick, but did not inherit the entire Warwick estate as his younger brother, Richard, Duke of Gloucester, had married (c. 1472) Anne Neville, who had been widowed in 1471. Edward intervened and eventually divided the estates between his brothers. Clarence was created, by right of his wife, first Earl of Warwick on 25 March 1472, and first Earl of Salisbury in a new creation.
In 1475 Clarence's wife Isabel gave birth to a son, Edward, later Earl of Warwick. Isabel died on 22 December 1476, two months after giving birth to a short-lived son named Richard (5 October 1476 – 1 January 1477). George and Isabel are buried together at Tewkesbury Abbey in Gloucestershire. Their surviving children, Margaret and Edward, were cared for by their aunt, Anne Neville, until she died in 1485 when Edward was 10 years old.