Rich was born in Buffalo, New York to Mabel A. (née Robinson) and william Martin Luther. She was raised in the Buffalo area and then Stites, Idaho, and Spokane, Washington with her older half-brother Edwin Darius Luther (1884-1961) and younger brother, Richard Robinson Luther.

She married Elvo Elcourt Deffenbaugh at All Saints' Cathedral in Spokane, Washington on February 17, 1909, after her parents talked about sending her to boarding school. Irene and Elvo had one child, Frances Rich, who became a stage and film Actress in the 1930s before becoming a noted Sculptor. Elvo was a salesman who traveled a lot. The young family moved to the Bay Area of San Francisco, where the marriage ended after two years.

Next she married Charles Henry Rich, who was then a lieutenant in the United States Army (became a major during World War I and was later a lieutenant colonel), in Portland, Oregon on January 9, 1912. The two had met when he was stationed with the 25th Infantry at Fort George Wright in Spokane. They had one daughter Martha Jane (b.December 13, 1916 in San Francisco). The marriage ended after four years. Luther went into real estate to feed herself and her two daughters. She then went to Hollywood in 1918 and got work as an extra.

Rich worked for Will Rogers, who used her in eight pictures, including Water Water Everywhere (1920), The Strange Boarder (1920), Jes' Call Me Jim (1920), Boys Will Be Boys (1921) and The Ropin' Fool (1921). She often portrayed society women, such as in the 1925 adaptation of Lady Windermere's Fan and also in Queen of the Yukon (1940).

Rich married for the third time on April 6, 1927, in Del Monte, California, to real estate mogul David Ferguson Blankenhorn (1886-1969), at the home of william May Garland. Blankenhorn was well known in the Los Angeles real estate market, was a longtime resident of Pasadena and San Francisco, and handled the transaction of william Wrigley, Jr. purchasing Catalina Island in 1919. Rich and Blankenhorn separated at least three times in the summer and fall of 1931, they filed for divorce on October 30, 1931, they were divorced that November.

In the 1930s, Rich did much work in radio. From 1933 to 1944, she hosted a nationwide anthology program of serialized mini-dramas, Dear John (aka The Irene Rich Show). Her leading man was actor Gale Gordon, (who later played Lucille Ball's apoplectic boss "Mr. Mooney" on TV). In the early 1940s, Rich starred in Glorious One on NBC Blue.

Rich appeared in stage productions, including Seven Keys to Baldpate (1935) which starred George M. Cohan, the creator of the play, and later As the Girls Go in 1948.

She became involved in a deadly love triangle in 1949 when Agnes Elizabeth Garnier shot and killed wealthy businessman John Edwin Owen (1881-1949). Owen, formerly a businessman and Politician from Michigan, was President of the National Apartment House Owner's Association, among other Business interests, including cattle and horse ranching in Gunnison, Colorado and Riverside, California. The Riverside County Sheriff's Department investigator said that Garnier killed Owen (who was married, but estranged and separated from his wife) and blamed Rich for coming between them. Garnier, Owen's personal secretary, told the district attorney that the gun went off accidentally and she took the gun from an intoxicated Owen as he was going to bed. Rich said that she was not in love with Owen and that they were just friends. Garnier, plead not guilty, the prosecutor decided not to try for first degree murder, and she was found guilty of manslaughter, and received a sentence of "one-to-ten" years. Garnier, after losing her appeal in January 1950, was released from Tehachapi Prison after serving less than a year-and-a-half, in May 1951. She died in San Diego in 1990 at the age of 93.

On February 28, 1950, Rich married George Henry Clifford (1881-1959), a public utilities executive, at the Sherry-Netherlands Hotel in New York City. He was President of Stone & Webster Service Corporation. The couple bought a ranch at Hope, near Santa Barbara, in 1956, where they lived out the remainder of their lives.

On April 22, 1988, Rich died at age 96 of heart failure in Hope Ranch, California.