Charlotte became queen consort at her marriage to George III in 1761 and was crowned with him that September. Her position combined court ceremony, family responsibilities and cultural patronage. She supervised the early education of their fifteen children through governesses and tutors, while the family divided its time among royal residences, including Buckingham House, Windsor and Kew. Her household brought her into contact with artists, writers and naturalists as well as courtiers.

Music occupied a prominent place in her patronage and private life. An accomplished keyboard player, she performed with the king and supported concerts at court. The young Mozart played before the royal couple in 1764 and dedicated six sonatas to her the following year. Her intellectual circle included the novelist Fanny Burney and naturalists Joseph Banks, Daniel Solander and John Lightfoot. At Kew she studied, catalogued and drew plants, sharing an interest in botany with other women in her circle.

George's severe illness in 1788–1789 transformed their domestic and public responsibilities. Charlotte accompanied the family to Kew during his treatment, and later recurrences increasingly separated their lives. When the Prince of Wales became regent in 1811, she was entrusted with guardianship of the king. She remained queen during the Regency, although her own health declined. Taken ill while travelling in 1818, she stayed at Kew, where she died in November after fifty-seven years as consort.