Imus was born in Riverside, California, the son of Frances E. (née Moore) and John Donald Imus, Sr. Imus and his younger brother, former talk show host Fred Imus, were raised on a sprawling cattle ranch, called The Willows, near Kingman, Arizona.
Imus served in the Marine Corps as a bugler from 1957 to 1960 and battled alcoholism during his early career in New York, but in 1987 finally pursued effective treatment. As of 2018, he had remained sober for 31 years. His act was reminiscent of pioneer shock-jock Petey Green's. In 1988, with his cocaine and alcohol addictions now legendary in show business, Imus reshaped his show from strictly comedy into a forum for political issues, charitable causes, and news-based parodies, largely inspired by Howard Stern's format.
In 1979, Imus and his first wife, Harriet, divorced. He married his second wife, Deirdre Imus (née Coleman) on December 17, 1994. Both Don and Deirdre are vegetarians.
He has two stepdaughters that he adopted from his first marriage (Nadine and Toni), two daughters from that marriage (Ashley and Elizabeth), three grandchildren and one son, Frederick Wyatt (nicknamed "Wyatt", born July 3, 1998), from his second marriage.
In 1999, Imus and Deirdre founded the Imus Ranch, a working 4,000-acre (16 km2) cattle ranch near Ribera, New Mexico, 50 miles (80 km) southeast of Santa Fe, for children with cancer and siblings of SIDS victims. Until its closing in 2014, the Imus family volunteered their time at the Imus Ranch between Memorial Day and Labor Day each year. Imus continued his broadcasts from a studio there, while the rest of his cast broadcast from New York.
In 2000, Imus suffered serious injuries after a fall from a horse at his ranch and broadcast several shows from a hospital. The injuries resulted in chronic breathing problems, especially at higher altitudes, he has complained on his program. In March 2009, Imus was diagnosed with stage 2 prostate cancer.
On his September 9, 2014, broadcast, he announced that the New Mexico ranch would be sold, due to his belief that the ranch had "run its course" as well as "health and other issues" (he specifically noted that his breathing had been damaged by a rib injury, making it difficult to breathe in New Mexico's high altitude). Proceeds from the property's sale would go to a 501(c)(3) charitable foundation that will donate to children's cancer causes. In October, 2014, the ranch was offered for sale with an asking price of $32 million. The ranch failed to sell after repeated efforts to do so, leading Imus to put the property up for auction in May 2017. When sold, Imus has earmarked all proceeds from the sale for the foundation.
Imus resides in Brenham, Texas, at a ranch he acquired in 2013. He moved there full-time in 2015, after ending his Fox Business television simulcast in New York and from there started broadcasting his show solely on radio with the cast members broadcasting from the WABC radio studios. His former waterfront mansion in Westport, Connecticut was sold that same year for $14.4 million.