[2] O'Brien made her first film appearance in Metro-Goldwyn-Mayer's Babes on Broadway (1941) at the age of four, but it was the following year that her first major role brought her widespread attention.

As a five-year-old in Journey for Margaret (1942), O'Brien won wide praise for her quite convincing acting style, unusual for a child of her age.

Also in 1943, at the age of seven, Margaret co-starred in "You, John Jones," a "War Bond/Effort," short film, with James Cagney and Ann Sothern (playing their daughter), in which she dramatically recited President Lincoln's "Gettysburg Address."

"[3] O'Brien‘s other successes included The Canterville Ghost (1944), Our Vines Have Tender Grapes (1945), Bad Bascomb (1946) with Wallace Beery, and the first sound version of The Secret Garden (1949).

O'Brien later shed her child star image, appearing on a 1958 cover of Life magazine with the caption "How the Girl's Grown",[4] and was a mystery guest on the TV panel show What's My Line?.

She appeared in S1 E39 "The Sacramento Story" of Wagon Train in 1958, playing Julie Revere, courted by Robert Horton's Flint McCullough.

She made a guest appearance on a 1963 episode of Perry Mason as Virginia Trent in "The Case of the Shoplifter's Shoe."

[9][10] In the years that followed, O'Brien attended memorabilia shows and searched antique shops, hoping she might find the original statuette, until one day in 1995 when Bruce Davis, then executive director of the Academy, was alerted that a miniature statuette bearing O'Brien's name had surfaced in a catalogue for an upcoming memorabilia auction.

[11] The two men decided to split the $500 asking price hoping to resell it at a profit and lent it to a photographer to shoot for an upcoming auction catalogue.

[9] This led to Bruce Davis' discovery that the statuette had resurfaced and, upon learning of the award's history, Nash and Neimand agreed to return the Oscar to O'Brien.

[12]In February 1960, O'Brien was honored with two stars on the Hollywood Walk of Fame, one for motion pictures at 6606 Hollywood Boulevard, and one for television at 1634 Vine St.[13] In 1990, O'Brien was honored by the Young Artist Foundation with its Former Child Star "Lifetime Achievement" Award recognizing her outstanding achievements within the film industry as a child actress.