De Salis was married three times.
His first marriage was to Sophia (1765 – 14 June 1803), daughter of Admiral Francis William Drake (1724–87), himself the brother of Sir Francis Henry Drake, 5th and last Baronet.
The couple were married on 12 August 1797 at Shirburn Castle, and had:
Peter John Fane de Salis, 5th Count de Salis-Soglio (St. Marylebone, February 1799 – 24 December 1870)
Four years after Sophia's death in 1803, De Salis married Penelope (died 20 December 1807), daughter of Dr. Robert Freeman, MD, of Uxbridge, on 14 March 1807 in Stoke Poges, and had one daughter:
Sophia Juliana Penelope de Salis (Langley, Buckinghamshire, December 1807 – 1866); married William Filgate of Lissrenny, co. Louth.
Mother of Charles Roden Filgate.

Penelope died shortly after the birth of their daughter.
A little over two years later, De Salis married Henrietta (Harriet) (9 October 1785 – 26 October 1856), daughter of Rt.
Rev. William Foster, DD (1744–97), who was chaplain to the Irish House of Commons (1780–89), and then variously Bishop of Cork and Ross; Kilmore; and of Clogher.
Harriet was the sister of John Leslie Foster, and a second cousin to one or two of the children of Lady Bess Foster.
Harriet's father was the brother of John Foster, of Collon, county Louth, Baron Oriel, and last Speaker of the Irish House of Commons.
The marriage took place on 10 May 1810 in St. Thomas's, Dublin.
The couple had nine children.

Rodolphus Johannes Leslie Hibernicus de Salis (Dublin, 9 May 1811 – Westminster 13 March 1880), Colonel of the 8th Hussars
William Andreas Salicus Fane De Salis (St. Marylebone, October 1812 – 3 August 1896)
(Nina) Catherina Barbara de Salis (Dublin, May 1814 – ); mother of John Warren, 3rd Baron de Tabley).

Leopold Fabius Dietegen Fane de Salis (Florence, 26 April 1816 – 20 November 1898), of Cuppacumbalong Homestead; went to New South Wales.

Henrietta Maria Felicitas de Salis (Paris, November 1817 – )
John Henry Anthony Gubertus (Paris, December 1818 – ); went to India;
Charles Louis Maximilian de Salis (Dublin, 1821 - Pimlico, July 1845); known as Captain the Hon.
C. Louis Fane De Salis.

Henrietta Emma Helena "Hadie" de Salis (Bath, 13 April 1826 - 16 August 1863); wife of Thomas-Chaloner Bisse-Challoner (11 December 1788 – 26 July 1872).

Rev. Count Henry Jerome Augustine Fane de Salis (Pisa, February 1828 - ), of Portnall Park, Virginia Water, formerly Rector of Fringford.
He was the father of Charles Fane de Salis.
De Salis was married three times. His first marriage was to Sophia (1765 – 14 June 1803), daughter of Admiral Francis William Drake (1724–87), himself the brother of Sir Francis Henry Drake, 5th and last Baronet. The couple were married on 12 August 1797 at Shirburn Castle, and had:
Peter John Fane de Salis, 5th Count de Salis-Soglio (St. Marylebone, February 1799 – 24 December 1870)
Four years after Sophia's death in 1803, De Salis married Penelope (died 20 December 1807), daughter of Dr. Robert Freeman, MD, of Uxbridge, on 14 March 1807 in Stoke Poges, and had one daughter:
Sophia Juliana Penelope de Salis (Langley, Buckinghamshire, December 1807 – 1866); married William Filgate of Lissrenny, co. Louth. Mother of Charles Roden Filgate.
Penelope died shortly after the birth of their daughter. A little over two years later, De Salis married Henrietta (Harriet) (9 October 1785 – 26 October 1856), daughter of Rt. Rev. William Foster, DD (1744–97), who was chaplain to the Irish House of Commons (1780–89), and then variously Bishop of Cork and Ross; Kilmore; and of Clogher. Harriet was the sister of John Leslie Foster, and a second cousin to one or two of the children of Lady Bess Foster. Harriet's father was the brother of John Foster, of Collon, county Louth, Baron Oriel, and last Speaker of the Irish House of Commons. The marriage took place on 10 May 1810 in St. Thomas's, Dublin. The couple had nine children.
Rodolphus Johannes Leslie Hibernicus de Salis (Dublin, 9 May 1811 – Westminster 13 March 1880), Colonel of the 8th Hussars
William Andreas Salicus Fane De Salis (St. Marylebone, October 1812 – 3 August 1896)
(Nina) Catherina Barbara de Salis (Dublin, May 1814 – ); mother of John Warren, 3rd Baron de Tabley).
Leopold Fabius Dietegen Fane de Salis (Florence, 26 April 1816 – 20 November 1898), of Cuppacumbalong Homestead; went to New South Wales.
Henrietta Maria Felicitas de Salis (Paris, November 1817 – )
John Henry Anthony Gubertus (Paris, December 1818 – ); went to India;
Charles Louis Maximilian de Salis (Dublin, 1821 - Pimlico, July 1845); known as Captain the Hon. C. Louis Fane De Salis.
Henrietta Emma Helena "Hadie" de Salis (Bath, 13 April 1826 - 16 August 1863); wife of Thomas-Chaloner Bisse-Challoner (11 December 1788 – 26 July 1872).
Rev. Count Henry Jerome Augustine Fane de Salis (Pisa, February 1828 - ), of Portnall Park, Virginia Water, formerly Rector of Fringford. He was the father of Charles Fane de Salis.
Jerome, 4th Count de Salis-Soglio