Webb was born Webb Parmelee Hollenbeck in Indianapolis, Indiana. He was the only child of Jacob Grant Hollenbeck (1867 – May 2, 1939), the ticket-clerk son of a grocer from an Indiana farming family, and his wife, the former Mabel A. Parmelee (Parmalee or Parmallee; March 24, 1869 – October 17, 1960), the daughter of David Parmelee, a railroad conductor. The couple married in Kankakee, Illinois, on January 18, 1888, and separated in 1891, shortly after their son's birth. According to Marion County, Indiana, marriage records, they married in Indianapolis on January 18, 1888.
In 1892, Webb's mother, now called "Mabelle", moved to New York City with her beloved "little Webb", as she called him for the remainder of her life. She dismissed questions about her husband, Jacob, who like her father, worked for the Indianapolis-St. Louis Railroad, by saying, "We never speak of him. He didn't care for the theatre." The couple apparently divorced, since by 1900, Mabelle was married to Green B. Raum, Jr. New York City's 1900 U.S. census indicates Mabelle and her son were using the surname Raum and living on West 77th Street with Green Berry Raum, Jr., a copper-foundry worker, who gave his position in the household as Mabel's husband. Raum was the son of General Green Berry Raum, former U.S. Commissioner of Internal Revenue and former U.S. Commissioner of Pensions. Webb's father, Jacob, married, as his second wife, Ethel Brown, and died in 1939.
By the age of 19, using the name Clifton Webb, he had become a professional ballroom dancer, often partnering "exceedingly decorative" star dancer Bonnie Glass (she eventually replaced him with Rudolph Valentino), and performed in about two dozen operettas before debuting on Broadway as Bosco in The Purple Road, which opened at the Liberty Theatre on April 7, 1913, and ran for 136 performances before closing in August.
The year 1917 proved to be better, with a 233-performance run of Jerome Kern's Love O' Mike, which opened at the Shubert Theatre on January 15, 1917. After moving to Maxine Elliott's Theatre and Casino Theatre, it closed on September 29, 1917. Future Mama star Peggy Wood was also in the cast. Webb's final show of the 1910s, the musical Listen Lester, had the longest run, 272 performances. It opened at the Knickerbocker Theatre on December 23, 1918, and closed in August 1919. Webb appeared with other Broadway stars in National Red Cross Pageant (1917), a 50-minute film of a stage production held to benefit the American Red Cross.
The 1920s had Webb in no fewer than eight Broadway shows, numerous other stage appearances, including vaudeville, and a handful of silent films. The revue As You Were, with additional songs by Cole Porter, opened at the Central Theatre on January 29, 1920, and closed 143 performances later on May 29, 1920. Busy with films, tours, and vaudeville, (including an appearance at the London Pavilion in 1921 as Mr. St. Louis in Fun of the Fayre and the next year in Phi-Phi), he did not return to Broadway until 1923, with the musical Jack and Jill (Globe Theatre) which had 92 performances between March 22, 1923, and June 9, 1923, and Lynn Starling's comic play Meet the Wife, which opened on November 26, 1923, and ran into the summer of 1924, closing in August. One of the play's leads was 24-year-old Humphrey Bogart.
In 1925, Webb appeared on stage in a dance act with vaudeville star and silent film actress Mary Hay. Later that year, when her husband, Tol'able David star Richard Barthelmess and she decided to produce and star in New Toys, they chose Webb to be second lead. The film proved to be financially successful, but 19 more years passed before Webb appeared in another feature film.
Webb's mainstay was the Broadway theatre. Between 1913 and 1947, the tall and slender performer who sang in a clear, gentle tenor, appeared in 23 Broadway shows, starting with major supporting roles and quickly progressing to leads. He introduced Irving Berlin's "Easter Parade" and George and Ira Gershwin's "I've Got a Crush on You" in Treasure Girl (1928); Arthur Schwartz and Howard Dietz's "I Guess I'll Have to Change My Plan" in The Little Show (1929) and "Louisiana Hayride" in Flying Colors (1932); and Irving Berlin's "Not for All the Rice in China" in the very successful revue As Thousands Cheer (1933). One of his stage sketches, performed with co-star Fred Allen, was filmed by Vitaphone as a short subject titled The Still Alarm (1930). Allen's experiences while working with Webb appear in Allen's memoirs.
Webb was in his mid-fifties when actor/director Otto Preminger chose him over the objections of 20th Century Fox chief Darryl F. Zanuck to play the elegant but evil radio columnist Waldo Lydecker, who is obsessed with Gene Tierney's character in the 1944 film noir Laura. (Zanuck reportedly found Webb too effeminate as a person and an actor.) His performance won him wide acclaim, and despite Zanuck's original objection, Webb was signed to a long-term contract with Fox. Two years later, he was reunited with Tierney in another highly praised role as the elitist Elliott Templeton in The Razor's Edge (1946). He received Academy Award nominations for Best Actor in a Supporting Role for both.
Webb also received an Oscar nomination for Best Actor in a Leading Role in 1949 for Sitting Pretty, the first in a three-film series of comedic Mr. Belvedere features with Webb portraying a snide, know-it-all babysitter.
In the 1950 film Cheaper by the Dozen, Webb and Myrna Loy played Frank and Lillian Gilbreth, real-life efficiency experts of the 1910s and 1920s, and the parents of 12 children. The film's success led to a sequel, Belles on Their Toes, with Webb appearing only in a cameo flashback, as the movie covers the family's life after the death of the father.
Webb's subsequent film roles include that of college professor Thornton Sayre, who in his younger days was known as silent-film idol Bruce "Dreamboat" Blair. Now a distinguished academic who wants no part of his past fame, he sets out to stop the showing of his old films on television in 1952's Dreamboat, which concludes with Webb's alter ego Sayre watching himself star in Sitting Pretty. Also in 1952, he starred in the Technicolor film biography of bandmaster John Philip Sousa, Stars and Stripes Forever. In 1953, he had his most dramatic role as the doomed but brave husband of unfaithful Barbara Stanwyck in Titanic, and in 1954 played the (fictional) novelist John Frederick Shadwell in Three Coins in the Fountain. The 1956 British film The Man Who Never Was had him playing the part of Royal Navy Lt. Cmdr. Ewen Montagu in the true story of Operation Mincemeat, the elaborate plan to deceive the Axis powers about the Allied invasion of Sicily during World War II. In 1957's Boy on a Dolphin, second-billed to Alan Ladd, with third-billed Sophia Loren, he portrayed a wealthy sophisticate who enjoyed collecting illegally obtained Greek antiquities. In a nod to his own identity, the character's name was Victor Parmalee.
Webb's final film role was an initially sarcastic, but ultimately self-sacrificing Catholic priest in Leo McCarey's Satan Never Sleeps. The film, which was set in China, showed the victory of Mao Tse-tung's armies in the Chinese Civil War, which ended with his ascension to power in 1949, but was actually filmed in Britain during the summer of 1961, using sets from the 1958 film The Inn of the Sixth Happiness, which had the same setting.
Webb was honored with a star on the Hollywood Walk of Fame at 6850 Hollywood Boulevard for his contributions to the motion picture industry.
Because of health problems, Webb spent the last five years of his life as a recluse at his home in Beverly Hills, California, eventually dying of a heart attack at the age of 76. He is interred in crypt 2350, corridor G-6, Abbey of the Psalms in Hollywood Forever Cemetery, alongside his mother.
Webb never married and had no children. He lived with his mother until her death at age 91 in 1960, leading Noël Coward to remark, apropos Webb's grieving, "It must be terrible to be orphaned at 71."
Actor Robert Wagner, who co-starred with Webb in the films Stars and Stripes Forever and Titanic and considered the actor one of his mentors, stated in his memoirs, Pieces of My Heart: A Life, that "Clifton Webb was gay, of course, but he never made a pass at me, not that he would have."