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The earliest evidence of habitation in the area dates back to ancient graves found near the Kype Water to the south of the district. Roman coins and footwear have also been found in the area.

East Kilbride takes its name from an Irish saint named St Bride (or Brigit), who founded a monastery for nuns and monks in Kildare, Ireland in the 6th century. Dal Riatan monks introduced her order to Scotland. The anglicisation Kil, takes its root from the early Celtic monastics that St. Brigit is representative of: the Culdees or Celi De. The Ceile De were 'the clients or companions of God'. In modern Gaelic, Cille Bhrìghde translates similarly as 'the clients or companions of Brigit.

The original parish church was located on the site of a pre-Christian sacred well, which is possibly the origin of the association with St. Brigit, since the well was dedicated to the Celtic goddess Brigid, whose traditions have been continued through the reverence of St. Brigit. Over the centuries, the church has been destroyed and rebuilt several times, and, as a result, its current location has moved from the original site by about 50 metres (160 ft).

The area of Calderglen was celebrated as a picturesque wooded valley. It was the home of a noble family known as the 'Maxwells of Calderwood' who resided in Calderwood Castle. The remnants of Calderwood Castle were demolished in 1951 and only a few parts of the structure remain.

East Kilbride grew from a small village of around 900 inhabitants in 1930 to eventually become a large burgh. The rapid industrialisation of the twentieth century underpins this growth and left much of the working population throughout Scotland's Central Belt, from Glasgow to Edinburgh, living in the housing stock built at the end of the previous century. The Great War postponed any housing improvements, as did the Treaty of Versailles and the period of post-war settlement it created. In turn, this was followed by the Great Depression. After the Second World War, Glasgow, already suffering from chronic housing shortages, incurred bomb damage from the war.

From this unlikely backdrop a new dawn emerged which would bring East Kilbride to its unlikely success. In 1946, the Clyde Valley Regional Plan allocated sites where overspill satellite "new towns" could be constructed to help alleviate the housing shortage. Glasgow would also undertake the development of its peripheral housing estates. East Kilbride was the first of five new towns in Scotland to be designated, in 1947, followed by Glenrothes (1948), Cumbernauld (1956), Livingston (1962) and Irvine (1964).

The town has been subdivided into residential precincts, each with its own local shops, primary schools and community facilities. The housing precincts surround the shopping centre, which is bound by a ring road. Industrial estates are concentrated on the outskirts of the town, in northern, western and southern directions.