Francis was the eldest son of Sir Thomas Englefield of Englefield House (Berkshire), Justice of the Court of Common Pleas, by Elizabeth the daughter of Sir Robert Throckmorton of Coughton Court (Warwickshire). His grandfather was Sir Thomas Englefield Senior, the Speaker of the House of Commons. Francis succeeded to the inheritance on his father's death on 28th September 1537. He was High Sheriff of Berkshire and Oxfordshire at the death of King Henry VIII and was dubbed a Knight of the Carpet at Edward VI's Coronation.

Francis became one of the chief officers in the household of the Princess Mary. On 14th August 1551, Robert Rochester, Comptroller of the Royal Household, Edward Waldgrave and Englefield appeared, in obedience to a summons, before the Privy Council at Hampton Court and received peremptory orders that mass should no longer be said in the Princess's house. Being afterwards charged with not obeying these injunc­tions, they were committed to the Fleet Prison and, on 31st August, sent to the Tower. On 18th March 1552, the three were permitted to leave the Tower for their health's sake and to go to their own homes; and, on 24th April 1552, they were set at liberty and had leave to repair to the Lady Mary at her request.

Upon Queen Mary's accession, Englefield was, in consideration of his faithful services, sworn onto the Privy Council and appointed Master of the Court of Wards and Liveries. He also obtained a grant of the manor and park of Fulbroke in Warwickshire - which were part of the lands forfeited by the attainder of John Dudley, Duke of Northumberland - and of Wootton Bassett in Wiltshire. He sat in the House of Commons as Knight of the Shire for the County of Berkshire in every parlia­ment held in Mary's reign. He was allowed, by the Queen, to have one hundred retainers. In January 1555, Sir Francis was present at the trial of Bishop Hooper. In May 1555, he was joined with others in a commission to examine certain persons who used the unlawful arts of conjuring and witchcraft and, in the following year, he was in another commission which was appointed to inquire into a conspiracy against the Queen. He often complained to Bishop Gardiner of Winchester, that Roger Ascham, Secretary for the Latin Tongue to Queen Mary, was a heretic and ought to be punished on that account or, at least, removed from his office; but the Bishop declined to take any action and remained a firm friend to Ascham throughout the Queen's reign.

Being a firm adherent of the Catholic religion, Sir Francis fled abroad in 1559, soon after the accession of Elizabeth, and retired to Valladolid in Spain. His lands and goods were seized for the Queen's use in consequence of his dis­obedience in not coming home after the Queen's revocation, and for consorting with her enemies. On 18th August 1563, he wrote to the Privy Council, expostulating and apolo­gising on account of his conscience, which “was not made of wax”. In 1563, being indicted in the Queen's Bench for high treason committed at Namur, Sir Francis was outlawed. Subsequently, he was attainted and convicted of high treason in Parliament on 29th October 1585 and all his manors, lands and vast possessions were declared to be forfeited to the Crown. Englefield had, however, by an indenture dated 1576, settled his manor and estate at Englefield upon his nephew, Francis Englefield Junior, with power notwithstanding to revoke the grant if he should deliver or tender a gold ring to the latter. Various disputes and points of law arose as to whether the Englefield estate was forfeited to the Queen. After protracted discussions in the law courts, the question remained undecided and, accordingly, in the ensuing Parliament (1592), Elizabeth had a special statute passed to confirm the attainder and to establish the forfeiture to herself. After tendering, by her agents, a ring to Englefield Junior, the nephew, she seized and confiscated the property. By this arbitrary stretch of power, the manor and estates of Englefleld, which had been for upwards of 780 years in the family, were alienated and transferred to the Crown. A full account of the legal pro­ceedings in this remarkable case is given by Lord Coke in his 'Reports'

After his retirement to Valladolid, the King of Spain allowed Sir Francis Senior a pension; and a great part of the collections for the English exiles were dispensed by him and his friend Dr. (afterwards Cardinal) Allen. On 8th April 1564, he wrote from Antwerp to the Privy Council, praying them to intercede with Elizabeth in his favour. He stated, at great length, his circumstances, the causes which had induced him to remain abroad, confuted the slanderous imputations against him and supplicated the Queen's forgiveness. In 1567, the King of Spain endeavoured, without success, to induce Elizabeth to allow Englefield the income of his estate, with permission to live abroad. The Queen ordered her ambassador in Spain to inform the King that none of her subjects were disturbed for their religion if they were quiet in the State. It is asserted, by Strype, that the Queen allowed Englefield the revenue of his estate in Eng­land and retained only a small part of it for the necessary maintenance of his wife.

In a list of English exiles, dated about 1575, in the State Paper Office it is stated that "Sir Frauncis Ingelfeld, knight, abideth commonly at Bruxelles; somme tyme he is at Machlin. He hath his owld pencion still, which he had beinge councellour in Queen Maries tyme, of the Kingof Spaigne, by moneth [no amount mentioned]. He rideth allwayes with 4 good horse" (Douay Diaries).

He stood high in the estimation of his exiled fellow-countrymen. Thus Dr. Nicholas Sander, writing in 1576 to the Cardinal of Como, classes Allen, with Englefield, as one of the two Catholics whom it would be a mistake not to consult in all questions concerning England. Sir Francis was engaged, in January 1586, in corresponding with the Pope and the King of Spain on behalf of Mary, Queen of Scots. In 1591, John Snowden, in a statement made to the English Govern­ment respecting Jesuits in Spain, says that Englefield “has six hundred crowns a year, and more if he demands it, and is entirely one with the Cardinal and Parsons”. For many years, he was afflicted with blindness. Writing in 1596, he remarks that more than twenty-four years had elapsed since he could write or read.

On 7th May 1598 Thomas Honyman, one of Cecil's spies, wrote that “postmasters in Spain weigh out the letters to their servants, and are easily corrupted for 28 ducats a month; the one at Madrid, Pedro Martinez, let me have all Cressold's and Englefield's letters, returning such as I did not dare to keep”. Englefield died about 1605 and was buried at Valladolid, where his grave was formerly shown, with respect, to English travellers.

He married Katherine the daughter and heiress of Sir Thomas Fettiplace of Compton Beauchamp (Berkshire), but had no issue. The family was continued by his brother, John Englefield of Vastern Manor in Wootton Basset (Wiltshire), whose son, the above mentioned Francis Junior, was created a baronet in 1612.