She was born Louise Byrdie Dantzler in Corsicana, Texas, the daughter of Taurrence J. Dantzler (December 1869 – March 18, 1906) and Louise B. (August 12, 1876 – April 3, 1973). Her brother was Taurrence J. Dantzler, Jr. (August 9, 1903 – April 6, 1973).

Her father died when she was one month old and the family later moved to Dallas. In the early 1920s, they moved to Long Beach, California. She had intended becoming an Illustrator but that was laid aside when at age 16 she was discovered in a local bathing beauty contest. One of the judges was famous motion picture star Esther Ralston (who was to play her mother in the upcoming Peter Pan and who became a lifelong friend).

After her showing in the beauty contest, she was given an audition by Paramount Pictures and cast by Director Herbert Brenon as Wendy Darling in his silent movie version of J. M. Barrie's Peter Pan (1924). There she starred with Betty Bronson and Esther Ralston, and the three of them stayed close for the rest of their lives. Ralston described both Bronson and Brian as 'very charming people'.

The studio, who created her stage name for the movie and said she was age 16 instead of 18, because the latter sounded too old for the role, then signed her to a long-term motion picture contract. Brian played Fancy Vanhern, daughter of Percy Marmont, in Brenon's The Street of Forgotten Men (1925), which had newcomer Louise Brooks in an uncredited debut role as a moll.

During her years at Paramount, Brian appeared in more than 40 movies as the lead, the ingenue or co-star. She worked with Brenon again in 1926 when she played Isabel in P. C. Wren's Beau Geste starring Ronald Colman. That same year she made Behind the Front and Harold Teen. In 1928, she played ingenue Alice Deane in Forgotten Faces opposite Clive Brook, her sacrificing father, with Olga Baclanova as her vixen mother and william Powell as Froggy. Forgotten Faces is preserved in the Library of Congress.

Her first talkie was Varsity (1928), which was filmed with part-sound and talking sequences, opposite Buddy Rogers. After successfully making the transition to sound, she co-starred with Gary Cooper, Walter Huston and Richard Arlen in one of the earliest Western talkies, The Virginian (1929), her first all-talkie feature. In it, she played a spirited frontier heroine, schoolmarm Molly Stark Wood, who was the love interest of the Virginian (Cooper).

Her final film of the 1930s was Affairs of Cappy Ricks although she auditioned unsuccessfully for the part that would go to Janet Gaynor in A Star is Born.

After her contract with Paramount ended in 1932, Brian freelanced. That same year, she appeared on the vaudeville stage at New York's Palace Theatre. Also in the same year, she starred in Manhattan Tower.

Other movie roles include Murial Ross, aka Murial Rossi, in Shadows of Sing Sing (1933), in which she received top billing, Gloria Van Dayham in College Rhythm (1934), Yvette Lamartine in Charlie Chan in Paris (1935), Hope Wolfinger, W. C. Fields’s daughter, in Man on the Flying Trapeze (1935), Sally Barnaby in Spendthrift (1936) opposite Henry Fonda, and Doris in Navy Blues (1937), in which she received top billing.

In 1936, she went to England and made three movies, including The Amazing Quest of Ernest Bliss in which she starred opposite Cary Grant, to whom she became engaged at one stage.

Brian was absent from the screen from 1937 to 1943. During World War II, she entertained servicemen in the South Pacific and in Europe. She spent Christmas of 1944 with the Soldiers fighting the Battle of the Bulge.

Though she was engaged numerous times and was linked romantically to numerous Hollywood men, including Cary Grant and notorious womaniser Jack Pickford, Brian had only two husbands: magazine Illustrator Jon Whitcomb (for six weeks, beginning May 4, 1941) and film Editor George Tomasini (from 1947 until his death in 1964). After retiring from the screen for good, she devoted herself to her husband's career; Tomasini worked as film Editor for Hitchcock on the classics Rear Window (1954) and Psycho (1960).

She appeared in only a handful of films thereafter. Her last performance on the silver screen was in Dragnet (1947), a B-movie in which she played Anne Hogan opposite Henry Wilcoxon. Over the course of 22 years, Brian had appeared in more than 79 movies.

During the 1950s, Brian had something of a career in television, most notably playing the title character's mother in Meet Corliss Archer (1954).

She played in the stage comedy Mary Had a Little... in the 1951 in Melbourne, Australia, co-starring with John Hubbard.

In 1960, Brian was inducted into the Hollywood Walk of Fame with a motion pictures star located at 1559 Vine Street.

She died of natural causes on December 30, 2002 at a retirement home in Del Mar, California at the age of 96. She is interred in the Eternal Love Section, Lot 4134, Space 2, Forest Lawn – Hollywood Hills Cemetery, Los Angeles, overlooking Burbank.