On May 20, 1818, William married Margaret Alida Rebecca Armstrong (1800–1872), the daughter of Senator John Armstrong Jr. and Alida (née Livingston) Armstrong and sister of Horatio Gates Armstrong.
 Her mother, a member of the prominent Livingston family, was the youngest child of Judge Robert Livingston and Margaret (née Beekman) Livingston as well as the sister of Chancellor Robert R. Livingston and Secretary of State Edward Livingston.
 Her father, John Armstrong Jr. was President James Madison's second Secretary of War.
Together, William and Margaret had seven children:
Emily Astor (1819–1841), who married Samuel Cutler "Sam" Ward (1814–1884), a financier/lobbyist/author, on January 5, 1838, and had two children.

John Jacob Astor III (1822–1890), who married Charlotte Augusta Gibbes (1825–1887) on December 9, 1846, and had one son.

Mary Alida Astor (1823–1881), who married John Carey (1821–1881) on April 16, 1850 and had three children.

Laura Eugenia Astor (1824–1902), who married Franklin Hughes Delano (1813–1893), on September 17, 1844 (no issue).

William Backhouse Astor Jr. (1829–1892), who married socialite Caroline Webster "Lina" Schermerhorn (1830–1908) on September 20, 1853, and had five children.

Henry Astor III (1830–1918), who married Malvina Dinehart (1844–1918) in 1871 (no issue).

Sarah Todd Astor (1832–1832), who died in infancy.

As a wedding gift, Astor gave Franklin and Laura Delano the southern-most 100 acres of Rokeby estate.
The estate came to be known as "Steen Valetje" (which means "little stone valley" in Dutch).

Margaret Astor died on February 15, 1872, William Astor survived his wife by three years dying on November 24, 1875 in his townhouse at Lafayette Place in New York City.
 He was buried next to his wife in the Astor vault at Trinity Church Cemetery, designed by Frederick Clarke Withers, in New York City.
In 1866 he conveyed the adjoining 142 acres of Rokeby to his son, Henry.
Henry Astor built a brick dwelling on this land, but in 1873 conveyed the property to Laura.


Astor's local newspaper The New York Times eulogised, 
Mr. William B. Astor.
an illness of four days ends an honored and successful life the public events in Mr. Astor's career a ripe scholar and philanthropic man.
 Mr William B. Astor, after an illness of only a few days, died at his residence in this City yesterday at 9:30 A.M., aged eighty three years.
Mr. Astor was in his usual good health, except for a slight cold, until Saturday of last week.
 On that morning his cold began to trouble him and occasioned a severe cough.
On May 20, 1818, William married Margaret Alida Rebecca Armstrong (1800–1872), the daughter of Senator John Armstrong Jr. and Alida (née Livingston) Armstrong and sister of Horatio Gates Armstrong.  Her mother, a member of the prominent Livingston family, was the youngest child of Judge Robert Livingston and Margaret (née Beekman) Livingston as well as the sister of Chancellor Robert R. Livingston and Secretary of State Edward Livingston.  Her father, John Armstrong Jr. was President James Madison's second Secretary of War. Together, William and Margaret had seven children:
Emily Astor (1819–1841), who married Samuel Cutler "Sam" Ward (1814–1884), a financier/lobbyist/author, on January 5, 1838, and had two children.
John Jacob Astor III (1822–1890), who married Charlotte Augusta Gibbes (1825–1887) on December 9, 1846, and had one son.
Mary Alida Astor (1823–1881), who married John Carey (1821–1881) on April 16, 1850 and had three children.
Laura Eugenia Astor (1824–1902), who married Franklin Hughes Delano (1813–1893), on September 17, 1844 (no issue).
William Backhouse Astor Jr. (1829–1892), who married socialite Caroline Webster "Lina" Schermerhorn (1830–1908) on September 20, 1853, and had five children.
Henry Astor III (1830–1918), who married Malvina Dinehart (1844–1918) in 1871 (no issue).
Sarah Todd Astor (1832–1832), who died in infancy.
As a wedding gift, Astor gave Franklin and Laura Delano the southern-most 100 acres of Rokeby estate. The estate came to be known as "Steen Valetje" (which means "little stone valley" in Dutch).
Margaret Astor died on February 15, 1872, William Astor survived his wife by three years dying on November 24, 1875 in his townhouse at Lafayette Place in New York City.  He was buried next to his wife in the Astor vault at Trinity Church Cemetery, designed by Frederick Clarke Withers, in New York City. In 1866 he conveyed the adjoining 142 acres of Rokeby to his son, Henry. Henry Astor built a brick dwelling on this land, but in 1873 conveyed the property to Laura.

Astor's local newspaper The New York Times eulogised, 
Mr. William B. Astor. an illness of four days ends an honored and successful life the public events in Mr. Astor's career a ripe scholar and philanthropic man.  Mr William B. Astor, after an illness of only a few days, died at his residence in this City yesterday at 9:30 A.M., aged eighty three years. Mr. Astor was in his usual good health, except for a slight cold, until Saturday of last week.  On that morning his cold began to trouble him and occasioned a severe cough.
William Backhouse Astor Sr.