Elsa Loacker Jones suggested that through his frequent travels, Drexel may have acquired considerable experience speculating in foreign exchange.

After his father's death in 1863, Francis Drexel became the senior member of the firm but preferred that his younger brother Anthony take the directorship.

Together, the parents of two children, Hannah died five weeks after the birth of their second daughter:[6] In 1860, he remarried to his second wife, Emma Mary Bouvier (1833–1883).

Although it was intended as a summer retreat, the family spent the better part of the year there from late spring to mid-autumn with Drexel taking the train to work.

[11] After a funeral at St. Mary's Catholic Church in Philadelphia, he was buried in the Drexel family vault at the Sisters of the Blessed Sacrament Cemetery.

Three days a week, Emma Drexel would distribute food, clothing, shoes, medicine, or rent money to any poor person who came to their door.

[14] Among Drexel's interest was Eden Hall, the Torresdale convent of the Society of the Sacred Heart where his wife, Emma, had attended the academy.

Drexel also donated the marble side altars for Sacred Heart Church in Wilmington, Delaware.

[16] Drexel left bequests to Saint Joseph's College, the House of the Good Shepherd, the Lutheran-run German Hospital of Philadelphia (where his brother-in-law John D. Lankenau was a trustee), St. John's Orphan Asylum for Boys, St. Joseph's Female Orphan Asylum where he had served both as a board member, and La Salle College,[17] which in 1886 relocated to the former mansion of Drexel's father-in-law, Michel Bouvier.

His daughters Elizabeth and Louise founded the St. Francis Industrial School at Eddington, Pennsylvania,[3] as provided in their father's will.