William was born in 1301, the eldest son of William Montacute, 2nd Baron Montacute (d. 1319) and his wife, Elizabeth, the daughter of Sir Piers de Montfort of Beaudesert in Warwickshire. William Junior succeeded his father as 3rd Baron on 6th November 1319, being granted wardship of his own lands, though yet a minor. In 1322, he came of age and received livery of his lands, together with a grant of Lundy Isle off the Devon coast. In 1325, he was knighted and received letters of protection on his departure for France. In 1327, he went with Edward III to repel the Scottish invasion, when the latter nearly missed capture. In 1329, he accompanied the King abroad and was sent, in June, to treat for a marriage between the eldest son of the King of France and Edward's sister, Eleanor. In September, he was despatched, with Bartholomew de Burghersh (d. 1355), on an embassy to the Pope at Avignon, returning before the end of the year, when, in his capacity as executor of Blanche, Queen of Navarre, he lent the King two thousand marks that had belonged to her, and were deposited at Whitefriars.

Next year, the young king took him into his confidence about his plans for the arrest of Mortimer. During the parliament held at Nottingham in October 1330, Montacute, with a band of retainers, including Sir John de Molines, penetrated by a secret passage into the castle, where they found Mortimer in the Queen-Mother's apartments. After a struggle, in which two of Mortimer's attendants were killed, his arrest was effected and he was sent to London for trial. Edward obtained, from Parliament, indemnity on Montacute's behalf for all consequences of the death of Mortimer's attendants, and rewarded him with various grants of land forfeited by Mortimer in Hampshire, Berkshire, Buckinghamshire, Kent and Wales, including Sherborne, Corfe Castle and Purbeck Chase in Dorset, and the lordship of Denbigh in North Wales. On 4th April 1331, Montacute accompanied Edward III when, disguised as a merchant and attended by only a handful of men-at-arms, the King paid a secret visit to France. He was also present when Edward repeated his homage to the French King at Amiens on 13th April, and returned with him to Dover on 20th April. In September, Montacute held a great tournament in Cheapside, entertaining his guests in the Bishop of London's palace.

Next year, he attended the King in Scotland and, in 1333, was present at the Siege of Berwick and the Battle of Halidon Hill. In the same year, Edward made over to him all his rights to the Isle of Man. He appears to have accompanied Balliol to Scotland and, in February 1334, was deputed by him to excuse his absence from the parliament held at York. On 30th March, Montacute was appointed envoy to France, with the Archbishop of Canterbury and two others; but, in June, was again in Scotland, where, in 1335, he was left in command of the army, with Arundel. In the same year, he was granted the forests of Selkirk and Ettrick and the town of Peebles, made Governor of the Channel Islands and Constable of the Tower of London, as well as acquiring Bisham Manor which, being so close to the King at Windsor, he made his principal family seat. In November, he was given power to treat with Andrew Murray, Constable of Scotland. On 27th January 1336, he commenced the Siege of Dunbar Castle, but, after nineteen weeks, the blockade was raised by Alexander Ramsay and Montacute gave it up in despair, making a truce that was strongly disapproved of in England. In the same year, he was appointed Admiral of the Fleet from the mouth of the Thames westward.

On 16 March 1337, at the parliament held in London, Montacute was created Earl of Salisbury. In the following April, he was sent to King Philip VI to declare Edward's claim to the French Crown, and thence on an embassy to the Emperor Louis, Rupert, Count Palatine, the Duke of Bavaria and other princes of Germany and the Netherlands, to organise a league against France. In October, he was commissioned to treat with Scotland, but, in July 1338, commanded a successful raid into Scotland from Carlisle. Later on in the year, he sailed, with Edward, from the Orwell to Flanders, and by a patent, dated Antwerp 20th September 1338, was appointed Marshal of England, an office then vacant by the death of Thomas, Earl of Norfolk. He remained in Flanders, where he was one of the captains of the English forces, for the next two years, during part of which he was in garrison at Ypres. In November 1338, he was one of those appointed to treat with Philip of Valois at the desire of the Pope. Shortly after, he made an inroad into the territories of the Bishop of Liege and, in February 1339, negotiated an agreement with the Archbishop of Treves and the Duke of Brabant, and was subsequently employed in various other negotiations. In 1340, induced, perhaps, by treachery within the walls, Salisbury and Suffolk, with a small force, made an attempt on Lille. The attack failed and both were taken prisoners and conveyed to Paris, when Salisbury, it is said, owed his life to the intervention of the King of Bohemia. On 18th October, Edward demanded a levy of wools to secure his liberation. He was set free - on condition of never serving against King Philip in France - at the peace negotiated after the Siege of Tournay, in exchange for the Earl of Moray, who had been captured in the Scottish Wars.

Salisbury returned to England in November and took part in Edward's arrest of the treasury officials and others. In May 1341, he was commissioned to investigate the charges against Stratford. Perhaps it was at this time that he conquered the Isle of Man from the Scots and was crowned King there; but the event has also been assigned to 1340 and 1342. In May 1343, Salisbury embarked, with Robert d'Artois, for Brittany, captured Vannes and proceeded to besiege Rennes. After the death of Artois and some months of ineffectual fighting, a truce was signed and, in August, Salisbury was sent on an embassy to the court of Castile. There, he took part in the Siege of Algeciras, which King Alfonso XI was then prosecuting against the Moors. He was soon recalled to England, however, and sent north against the Scots. He died on 30th January 1344 from bruises, it is said, received during a tournament held at Windsor, and was buried at Bisham Priory which he had founded in 1337. He married Katharine, daughter of Sir William Grandisson, by whom he had two sons, William, 2nd Earl of Salisbury, and John, and four daughters, one of whom, Philippa, married Roger Mortimer, 2nd Earl of March