Early in the reign of Edward IV, Oxford's father, the 12th Earl, and his elder brother were executed for plotting against the king (1462). However, Edward was pursuing a policy of conciliation with Lancastrian families, and de Vere was allowed to succeed to his father's estates and titles. He was allowed to assume his family's traditional role as Lord High Chamberlain, officiating in that capacity at the coronation of Edward's queen, Elizabeth Woodville, in 1465. Around the same time he married Margaret Neville, a sister of Richard Neville, Earl of Warwick.
In 1468 Oxford was caught in a plot against the king. He spent a short time in the Tower of London, but was released and pardoned early in 1469. He probably avoided execution due to the influence of his brother-in-law. Oxford was very likely quietly involved in Warwick's schemes against Edward in 1469 and 1470. In the latter year he fled to Margaret of Anjou's court in exile in France. Given his position as the leader of a steadfast Lancastrian family and also as Warwick's brother-in-law, Oxford negotiated the switch of Warwick to the Lancastrian side. He returned to England when Henry VI was restored in 1470. Oxford was appointed Constable of England.
Oxford was one of the Lancastrian commanders at the Battle of Barnet (1471). After this defeat, and the death of Warwick, he fled again, this time to Scotland and then to France. With a little aid from Louis XI of France he took to piracy against English ships and the occasional raid on the coast. Then came the most puzzling incident of Oxford's career. In 1473 he seized St Michael’s Mount, a small rocky island off the coast of Cornwall. His motives are not clear. Most likely, this was to be the prelude to an invasion of England intending to depose Edward and put his brother, George, Duke of Clarence, on the throne. No invasion or help came, and in early 1474 he surrendered. Oxford was imprisoned in the fortess of Hammes, near Calais.
Three years later, Oxford lept off the walls of Hammes into the chin-deep moat. Whether he meant to escape or to kill himself is not known; he accomplished neither. He remained imprisoned there until 1484, when he persuaded the captain of Hammes, Sir James Blount to escape with him to the court in exile of Henry Tudor (later Henry VII of England). It is said that Henry was "ravished with joy incredible" at this event. As by far the most experienced Lancastrian, Oxford was the real commander at the Battle of Bosworth Field, though Henry was theoretically in charge. Oxford commanded the center, and held off the downhill charge of the Earl of Northumberland at the beginning of the battle.
Oxford was now restored to his estates and titles, and was also appointed Lord High Admiral and Constable of the Tower. His fighting days were not quite over. Two Yorkist pretenders invaded England in the early years of Henry's reign. Oxford commanded the vanguard at the Battle of Stoke Field (the only part of the royalist army that actually had to fight), and was then commander in chief at the Battle of Blackheath.
Oxford was succeeded as Earl by his nephew.