The town of Mylapore predates British rule by several centuries. It was historically known as Vedapuri. As the available historical and archaeological evidence shows, it could well be the oldest part of Chennai, with written records of early settlements going back to the first century BC. It was known for its ancient port with a flourishing trade with the Roman Empire, receiving gold in exchange for its products like pepper and fine cloth. Ptolemy had recorded in the 2nd century AD that the port of Mylapore was known to the Greeks and the Romans. Mention has been made of the early settlement of Santhome by Arab travelers and merchants of the 9th and 10th centuries AD. Marco Polo visited the place in the late 13th century, and the Portuguese settled around Santhome in the early 16th century.

Mylapore was occupied by the Portuguese in 1523, who established the viceroyalty of "São Tomé de Meliapore" or "Saint Thomas of Mylapore." Portuguese rule lasted until 1749, except for a brief interregnum between 1662 and 1687, when the town was occupied by the French.

After 1749, the town fell into the hands of the British East India Company, who took possession of the settlement in the name of Muhammad Ali Khan Wallajah, the Nawab of Arcot. In that same year, Mylapore was incorporated into the administration of the Presidency of Madras. The settlement known as "Luz" developed during this period. As early as 1760, an English writer by the name of James Taylor applied for land in the region known as "Luce." The name "Luz" might have originated from this.

In the late 19th and early 20th centuries the town became the commercial and intellectual hub of Madras city and home to British-educated lawyers and statesmen. Some of the luminaries based in Mylapore included Sir V. Bhashyam Aiyangar, Sir S. Subramania Iyer, Sir T. Madhava Rao, Eardley Norton, Sir P. S. Sivaswami Iyer, Pennathur Subramania Iyer, V. Krishnaswamy Iyer,Sir C. P. Ramaswami Iyer, H Bhimasena Rau, C S Rama Rao Sahib, Subanthore Vasudeva Rao, CR Krishnaswamy Rao Sahib and the civil engineer C R Narayana Rao. Subanthore Vasudeva Rao's descendants still reside in his 100-year-old house near Kapaleeswarar Temple, Mylapore.

In recent times, increasing commercialization has changed the look of the area. Today, Mylapore is known for its residential colonies, temples, shopping malls, music halls and sabhas, along with old 19th century style residential buildings and houses.