By 1710 Lady Mary had two possible suitors to choose from: Edward Wortley Montagu and Clotworthy Skeffington. Mary's father, now Marquess of Dorchester, rejected Wortley Montagu as a prospect because he refused to entail his estate on a possible heir. Her father pressured her to marry Clotworthy Skeffington, heir to an Irish peerage. Although Lady Mary had fallen in love with another unidentified man, in order to avoid marriage to Skeffington, she eloped with Wortley. They were married on 23 August 1712 in Salisbury.
The early years of Lady Mary Wortley Montagu's married life were spent in seclusion in the country. She had a son, Edward Wortley Montagu the younger, on 16 May 1713, in London. Her husband became Member of Parliament for Westminster in 1715, and shortly afterwards was made a Lord Commissioner of the Treasury. When Lady Mary joined him in London, her wit and beauty soon made her a prominent figure at court. She was among the society of George I and the Prince of Wales, and counted amongst her friends Molly Skerritt, Lady Walpole, John, Lord Hervey, Mary Astell, Sarah Churchill, Duchess of Marlborough, Alexander Pope, John Gay, and Abbé Antonio Conti.
In December 1715, Lady Mary contracted smallpox. She survived, but while she was ill someone circulated the satirical “court eclogues” she had been writing. One of the poems was read as an attack on Caroline, Princess of Wales, in spite of the fact that the "attack" was voiced by a character who was herself heavily satirized. Disgraced and unable to return to court, Lady Mary left London in August 1716 to accompany her husband on his embassy to Istanbul.
Early in 1716, Edward Wortley Montagu was appointed Ambassador at Istanbul. Lady Mary accompanied him to Vienna, and thence to Adrianople and Istanbul. He was recalled in 1717, but they remained at Istanbul until 1718. She had a daughter, who would grow up to be Mary, Countess of Bute, on 19 January 1718 in Istanbul. After an unsuccessful delegation between Austria and Ottoman empires, they returned to England.
The story of this voyage and of her observations of Eastern life is told in Letters from Turkey, a series of lively letters full of graphic descriptions; Letters is often credited as being an inspiration for subsequent female traveller/writers, as well as for much Orientalist art. During her visit she was sincerely charmed by the beauty and hospitality of the Ottoman women she encountered, and she recorded her experiences in a Turkish bath with a keen eye for detail. While in Turkey, she also recorded a particularly amusing incident in which a group of Turkish women, horrified by the sight of the corset she was wearing, exclaimed that "the husbands in England were much worse than in the East, for [they] tied up their wives in little boxes, the shape of their bodies". Lady Mary wrote that nowhere else were women as free as they were in the Ottoman Empire.
Lady Mary returned to the West with knowledge of the Ottoman practice of inoculation against smallpox, known as variolation. In the 1790s, Edward Jenner developed a safer method, vaccination. In 1727 her husband inherited Wortley Hall, near Barnsley, Yorkshire, and commissioned a major remodelling of the house in 1742.