In 1775, she sang oratorio at Covent Garden and began the role of Clara in Richard Brinsley Sheridan's The Duenna. However, although she was in great demand as Clara, she ran away from the theatre with the playwright and gunpowder maker Miles Peter Andrews. She was only fifteen years old, and the scandal of their affair prompted Ann's father to get a court order restraining her to his house, but Ann had run away in response. The next autumn, she was contracted to sing the role of Polly in The Beggar's Opera, the prima donna role, and thus, in the fall of 1776 her father intercepted her as she entered the theatre. However, the crowd restrained her father's men and demanded that she enter.
In 1779 and 1780, she was receiving ten pounds sterling a week as a singer, but she eloped with a Mr. Cargill to Edinburgh. Mr. Cargill was a Scotsman who had dabbled in the theatre and who was using the name of "Mr. Doyle" to evade his creditors. In 1781, she returned to London and sang at the Haymarket Theatre in the summers and the Drury Lane Theatre in the winters as Mrs. Cargill. In 1781, she was enormously popular in the role of Macheath in a cross-gendered production of The Beggar's Opera at Drury Lane, where all the male roles were played by women and all the female roles by men. She then ran off to Bath with her husband for the summer, returning for the breeches role of Patie in Allan Ramsay's The Gentle Shepherd and the female role of Marinetta in Richard Tickell and Thomas Linley's Carnival of Venice.
George Colman the Younger sued Mr. and Mrs. Cargill for breach of contract for having switched theatres. When a court heard the case in 1781, it found that both of the defendants had been under twenty-one when they had signed their contracts, and therefore that the contracts were not enforceable. Ann Cargill, now at the height of her fame, went on tour. She played the summer of 1782 in Liverpool.
By 1783, she had a new love. Her lover was in the British East India Company and stationed in Calcutta, so she left England for India. In 1783, she performed operatic parts in Calcutta, to tremendous applause, and her benefit night brought in "the astonishing sum of 12,000 rupees" (Baldwin and Wilson, 93). At the end of 1783, she took ship back to England on a ship with the same name as Henry Carey's 1739 opera, the Nancy.
Her ship wrecked and sank off the Isles of Scilly in February of 1784. Her body was found, dressed in a chemise, with an infant clutched in her arms. She was buried on Rosevear Island then reburied at Old Town Church on St Mary's in the Isles of Scilly, and newspaper accounts of her death and her "floating in her shift" with an infant at her bosom made her a tragic figure for the English press. In September 2008, British divers claimed to have found the wreck of the Nancy, further out from the Isles of Scilly than was previously thought.