McBride was born on November 16, 1899 in Paris, Missouri, to a farming family. Their frequent relocations disorganized her early schooling, but at the age of six she became a student at a preparatory school called William Woods "College", and at 16 the University of Missouri, receiving a degree in journalism there in 1919.

She worked a year as a reporter at the Cleveland Press, and then until 1924 at the New York Evening Mail. Following this, she wrote freelance for periodicals including the Saturday Evening Post, Cosmopolitan, Good Housekeeping, and starting in 1926 collaborated in writing travel-oriented books.

McBride first worked steadily in radio for WOR in New York City, starting in 1934. This daily women's-advice show, with her persona as "Martha Deane", a kind and witty grandmother figure with a Missouri-drawl, aired daily until 1940.

Concurrently with working as "Deane", in 1934 and '35, she served the syndicate Newspaper Enterprise Association as women's page editor. And in 1937, she launched on the CBS radio network the first of a series of similar and successful shows, now as Mary Margaret McBride.

She interviewed figures well known in the world of arts and entertainment, and politics, with a style recognized as original to herself. She accepted advertising only for products she was prepared to endorse from her own experience, and turned down all tobacco or alcohol products.

She followed this format in regular broadcasts on

• CBS until 1941
• NBC (where her audience numbered in the millions) from then until 1950
• ABC from then until 1954
• NBC again until 1960, and
• the New York Herald Tribune's radio broadcasts, with a wider audience via syndication.

Her NBC show in the 1940s had broad range of guests, from politicians to generals to movie stars; she never announced her guests in advance, so the audience tuned in with no idea what they would get. Beginning during World War II, she began "breaking the color line", mixing in African American guests.

In September 1948, NBC brought McBride to television for a 30-minute prime time show on Tuesdays at 9pm EST. However, NBC abandoned the show in its partial third month, with Variety describing the attempt sarcastically, and the New York Times calling her the first major "fatality" of this kind.

From 1953 to 1956 she also conducted a syndicated newspaper column for the Associated Press.

About twenty years apart, she wrote two books for girls, each with "Elizabeth" in the title.

As time went on, she appeared in smaller radio media markets, in upstate New York, and toward the end of her life hosted "Your Hudson Valley Neighbor" three times a week on WGHQ Kingston, NY from the living room of her home. Her longtime companion and business partner, Stella Karn, died of cancer in 1957.

McBride died at the age of 76 on April 7, 1976 at West Shokan, New York.

An account of her career, It's One O'clock and Here is Mary Margaret McBride: A Radio Biography by Susan Ware was published in early 2005. She is also discussed in depth in Radio Voices by Michele Hilmes.

The character of "Mary McGoon", featured in the comedy routines of Bob and Ray, is a parody of Mary Margaret McBride.

Her name was spoofed on the classic CBS-TV sitcom I Love Lucy in Episode # 79, "The Million Dollar Idea", which aired on January 11, 1954. In that installment, Lucy (Lucille Ball) comes up with an ambitious idea to make money. She decides to appear on television selling her Aunt Martha's salad dressing. Assisting her on the program is her best friend Ethel Mertz (Vivian Vance) as "Mary Margaret McMertz."