Reginald was a grandson of william Henry Vanderbilt (1821–1885), and great-grandson of Commodore Cornelius Vanderbilt (1794–1877).
He attended Yale University, but did not graduate. His eldest brother, Cornelius Vanderbilt III (1873–1942), married Grace Wilson against his parents' wishes and was disinherited. Another elder brother, Alfred, inherited the bulk of the family fortune, though Reginald and several sisters also received some inheritance.
Reginald Claypoole Vanderbilt was born on January 15, 1880, on Staten Island, New York. He was the youngest son of Cornelius Vanderbilt II (1843–1899) and Alice Claypoole Gwynne (1845–1934). Among his siblings was Gertrude Vanderbilt (1875–1942), who married Harry Payne Whitney, Alfred Gwynne Vanderbilt (1877–1915), and Gladys Moore Vanderbilt (1886–1965), who married Count László Széchenyi.
In 1903, Reginald married Cathleen Neilson (1885–1927) at Parker Cottage in Newport, Rhode Island. She was the niece of Frederick Gebhard (c. 1860–1910), and the great-granddaughter of Thomas E. Davis, a prominent New York real estate developer. Before their divorce in 1920, the couple had one daughter:
Through his eldest daughter, Vanderbilt was the grandfather of Henry Cooke Cushing IV (1923–2000), who was married to Georgia Walters "Georgette Windsor" (b. 1924), Ruth Swift Dunbar (1932–2010), Rosalba Neri (b. 1939), and Laura Alvarez.
He died from cirrhosis due to alcoholism on September 4, 1925, at his country home, Sandy Point Farm, in Portsmouth, Rhode Island. In his will, he left the vast majority of his estate to his daughters with a residue to his widow, which was not to exceed $1,125,000 and his New York townhouse, located at 12 East 77th Street, and Sandy Point farm.
Through his daughter Gloria, Reginald is the maternal grandfather of Leopold Stanislaus Stokowski (b. 1950), who married Ivy Strick and Emily Goldstein (b 1964), Christopher Stokowski (b. 1952), Carter Vanderbilt Cooper (1965–1988), and Anderson Hays Cooper (b. 1967), the television news anchor.