Perle Skirvin grew up in an affluent family in Oklahoma City and was educated privately. In 1917 she married George Mesta, a wealthy Pittsburgh, Pennsylvania, manufacturer. While he was working in Washington, D.C., during World War I, she had her first introduction to politics and Washington society. After the war the Mestas traveled extensively in Europe, and by the time of her husband's death in 1925 Perle Mesta had a large acquaintanceship in the worlds of business and politics.

In 1929 Mesta settled in Newport, Rhode Island, where she soon became a leading hostess. About 1935 she began to devote much time to active political work. She joined the National Woman's Party and became an effective lobbyist on behalf of the Equal Rights Amendment; she was also chairman of the party's public relations committee for a time. In electoral politics Mesta supported the Republican Party until 1940 and the Democratic Party thereafter. About 1940 she moved her residence to Washington, D.C., and soon became one of the capital's foremost hostesses. She was an early patron of Senator Harry S. Truman (Truman, Harry S.) and was greatly helpful to him in the elections of 1944 and, especially, 1948, when she served on the finance committee of the Democratic campaign. In 1949 Mesta became U.S. minister to Luxembourg. She was the first to hold the post, diplomatic relations with the duchy having previously been handled by the ambassador to Belgium. She served in the post until 1953.

Mesta's appointment inspired Irving Berlin (Berlin, Irving)'s hit musical Call Me Madam, in which Ethel Merman (Merman, Ethel) starred (1950–52). During the 1950s Mesta remained Washington's premier hostess as the informal charm and gaiety of her entertaining attracted the cream of international society. The advent of a new social atmosphere with the Kennedy administration, however, started a decline in her influence. In 1960 she published Perle: My Story.