James Eads married Eunice Hagerman Eads on May 2, 1854, a year and a half after his first wife Martha died. Eunice was the widow of Eads' first cousin, Elijah Clark Eads. Eunice and James had long been good friends. In 1849, after Elijah died, leaving Eunice very little money, Eads rescued her from an unpleasant living situation, helping Eunice pay the rent in more comfortable lodging.

Although, to some observers the marriage was one of convenience -- after all, Eads did need a wife to help run his household and look after his two daughters -- from their correspondence Eunice and James appear to have been an affectionate couple. In one long, loving letter, Eads wrote: "I can not rest day nor night until I shall have the pleasure of seeing you, and enjoying your company. You are all to me, and your happiness is all that I live for."