In 1930, Christie married archaeologist Max Mallowan after joining him in an archaeological dig. Their marriage was especially happy in the early years and remained so until Christie's death in 1976. In 1977, Mallowan married his longtime associate, Barbara Parker.

Christie frequently used familiar settings for her stories. Christie's travels with Mallowan contributed background to several of her novels set in the Middle East. Other novels (such as And Then There Were None) were set in and around Torquay, where she was born. Christie's 1934 novel Murder on the Orient Express was written in the Hotel Pera Palace in Istanbul, Turkey, the southern terminus of the railway. The hotel maintains Christie's room as a memorial to the author. The Greenway Estate in Devon, acquired by the couple as a summer residence in 1938, is now in the care of the National Trust. Christie often stayed at Abney Hall in Cheshire, which was owned by her brother-in-law, James Watts. She based at least two of her stories on the hall: the short story The Adventure of the Christmas Pudding, which is in the story collection of the same name, and the novel After the Funeral. "Abney became Agatha's greatest inspiration for country-house life, with all the servants and grandeur which have been woven into her plots. The descriptions of the fictional Chimneys, Stoneygates, and other houses in her stories are mostly Abney in various forms."

During the Second World War, Christie worked in the pharmacy at University College Hospital of University College, London, where she acquired a knowledge of poisons that she put to good use in her post-war crime novels. For example, the use of thallium as a poison was suggested to her by UCH Chief Pharmacist Harold Davis (later appointed Chief Pharmacist at the UK Ministry of Health), and in The Pale Horse, published in 1961, she employed it to dispatch a series of victims, the first clue to the murder method coming from the victims’ loss of hair. So accurate was her description of thallium poisoning that on at least one occasion it helped solve a case that was baffling doctors.

To honour her many literary works, she was appointed Commander of the Order of the British Empire in the 1956 New Year Honours. The next year, she became the President of the Detection Club. In the 1971 New Year Honours she was promoted Dame Commander of the Order of the British Empire, three years after her husband had been knighted for his archeological work in 1968. They were one of the few married couples where both partners were honoured in their own right.

From 1971 to 1974, Christie's health began to fail, although she continued to write. Recently, using experimental, computerised, textual tools of analysis, Canadian researchers have suggested that Christie may have begun to suffer from Alzheimer's disease or other dementia. In 1975, sensing her increasing weakness, Christie signed over the rights of her most successful play, The Mousetrap, to her grandson.

Agatha Christie died on 12 January 1976 at age 85 from natural causes at her Winterbrook House in the north of Cholsey parish, adjoining Wallingford in Oxfordshire (formerly Berkshire). She is buried in the nearby churchyard of St Mary's, Cholsey.

Christie's only child, Rosalind Margaret Hicks, died, also aged 85, on 28 October 2004 from natural causes in Torbay, Devon. Christie's grandson, Mathew Prichard, was heir to the copyright to some of his grandmother's literary work (including The Mousetrap) and is still associated with Agatha Christie Limited.

Agatha Christie's first novel The Mysterious Affair at Styles was published in 1920 and introduced the long-running character detective Hercule Poirot, who appeared in 33 of Christie's novels and 54 short stories.

Her other well known character, Miss Marple, was introduced in The Tuesday Night Club in 1927 (short story) and was based on women like Christie's grandmother and her "cronies".