On June 29, 1850 Rice married Margaret Bremond, age 18, whose father Paul Bremond was one of Rice's many business partners.
They were married in Houston's Christ Church, with an elegant reception afterwards at the Capitol Hotel. The couple then honeymooned on the Eastern seaboard. Little is known about Margaret Bremond Rice's life married to William Marsh Rice, beyond several newspaper reports of social and philanthropic activities.
As Rice began to focus more keenly on making money through cotton, his wife worked in the war-relief effort. The Rice name appeared regularly on the lists of those who contributed to patriotic causes during the war, and in 1862, Wm. M. Rice and Co. donated funds toward the purchase of a home for the widow and children of a decorated soldier who perished on the battlefield. William also made donations for the relief of volunteers’ families.
On August 13, 1863 Margaret Bremond Rice died, possibly from cholera or yellow fever.
On June 26, 1867 Rice married for a second time. His second wife was Julia Elizabeth Baldwin Brown, a widow and a daughter of Horace Baldwin, one of the early mayors of Houston. Elizabeth's sister Charlotte was the wife of William's younger brother Frederick.
Rice and his second wife moved to New Jersey to live with Rice's sister Charlotte and her family. Rice and his wife divided their time between New York City and New Jersey with occasional trips to Houston to oversee business.