His father, with whom he had little interaction, died when he was six years old. William Matthews Sr.'s ancestry traces to the English landed gentry, and includes Thomas Matthews—an early settler of the Maryland colony who was granted of land in Port Tobacco, Maryland, by the Lords Calvert. His mother descended from Captain James Neale, who settled in the Maryland colony in the mid-seventeenth century. Matthews' matrilineal ancestry traces its origins to the noble O'Neills of Ireland. His cousin, Charles Carroll of Carrollton, was the sole Catholic signatory of the Declaration of Independence. In 1781, aged eleven, he witnessed British troops burn part of his family's estate during the American Revolution. He eventually became the maternal uncle of Senator Richard T. Merrick and Judge William Matthews Merrick, and the brother-in-law of Senator William Duhurst Merrick. From his parents, Matthews received a sizable inheritance that he drew from throughout his life for the advancement of the church. Many of Matthews' matrilineal relatives entered the priesthood. Six of his mother's seven brothers became Jesuits, and one died during the Jesuit novitiate. His uncle, Bennett Neale, was one of the first Jesuits in the English colony. His other maternal uncles were: Francis Neale, who both preceded and succeeded him as president of Georgetown College; Leonard Neale, the Archbishop of Baltimore and also president of Georgetown; and Charles Neale, the superior of the Jesuits in America. His aunt, Ann Mathews, and two of his sisters—Susanna (Sister Mary Eleanora) and Ann Teresa (Sister Mary Aloysia)—became Carmelite nuns. Matthews was sent, aged twelve, to Liège in the Prince-Bishopric of Liège (modern-day Belgium) to be educated at the College of St Omer, an English Jesuit school, where he studied classics. This made him one of the last Americans to be sent to the English school at Liége. He returned to America in his early twenties to briefly study theology at Georgetown College. While at Georgetown in 1796, he was chosen to be the first student to greet President George Washington upon his visit to the college. He entered St. Mary's Seminary in Baltimore in 1797. Although a student at St. Mary's Seminary, Matthews frequently served as an instructor of English at Georgetown College because the professors and seminarians at St. Mary's were asked by Bishop John Carroll to assist with the teaching duties of the Jesuits at Georgetown.