Machen was married three times and was widowed twice. Machen married firstly Margaret Aurelia Lyon (1819-1852), daughter of U.S. Representative Chittenden Lyon and granddaughter of U.S. Representative Colonel Matthew Lyon, on December 28, 1835. They had at least six children: a daughter, Mary J. Machen (1838-1854) and five sons, Edward Chittenden Machen (1840-1845), Henry Lyon Machen (1843-1893), Edward C. Machen (1846-after 1887), Willis Benson Machen Jr. (1849-1851) and Willis Benson Machen III (1851-1852). His wife died in 1852 and in the same year he married his second wife Eliza N. Dobbins (1829-1859). They had three children: one son, John S. Machen and two daughters, Mary E. Machen and Elizabeth Machen. He was again widowed in 1859. He married thirdly Victoria Theresa Mims (1838-1895), daughter of John Harrison Mims and Caroline Hanson (Cresap) Mims, on September 10, 1859. They had eight children (at least three died in childhood): sons, Frank P. Machen, Willis B. Machen (IV) (1872-1903), Charles Victor Machen and Albert Sidney Machen (1875-1876) and daughters, Minerva Buckner "Minnie" (Machen) Sayre (1860-1958) (the wife of Anthony D. Sayre and mother of Zelda Sayre Fitzgerald), Maggie Davis Machen (1862-1864), Caroline Mims Machen (1874-1874) and Marjorie Lee (Machen) Rieke (1881-1913).