The area of Karachi was known to the ancient Greeks by many names: Krokola, the place where Alexander the Great camped to prepare a fleet for Babylonia after his campaign in the Indus Valley; 'Morontobara' (probably Manora island near Karachi harbour), from whence Alexander's admiral Nearchus set sail; and Barbarikon, a port of the Bactrian kingdom. It was later known to the Arabs as Debal from where Muhammad bin Qasim led his conquering force into South Asia in 712 AD[14]

Karachi was founded as "Kolachi" by Sindhi and Baloch tribes from Balochistan and Makran, who established a small fishing community in the area.[15] Descendants of the original community still live in the area on the small island of Abdullah Goth, which is located near the Karachi Port.The original name "Kolachi" survives in the name of a well-known Karachi locality named "Mai Kolachi" in Sindhi. Mirza Ghazi Beg, the Mughal administrator of Sindh, is among the first historical figures credited for the development of Coastal Sindh (consisting of regions such as the Makran Coast and the Mehran Delta), including the cities of Thatta, Bhambore and Karachi.

During the rule of the Mughal administrator of Sindh, Mirza Ghazi Beg, the city was well fortified against Portuguese colonial incursions in Sindh. During the reign of the Kalhora Dynasty, the present city started life as a fishing settlement when a Sindhi Balochi fisher-woman called Mai Kolachi took up residence and started a family. The city was an integral part of the Talpur dynasty in 1720.

The village that later grew out of this settlement was known as Kolachi-jo-Goth (Village of Kolachi in Sindhi). By the late 1720s, the village was trading across the Arabian Sea with Muscat and the Persian Gulf region. The local Sindhi populace built a small fort, that was constructed for the protection of the city, armed with cannons imported by Sindhi sailors from Muscat, Oman. The fort had two main gateways: one facing the sea, known as Kharra Darwaaza (Brackish Gate) (Kharadar) and the other facing the Lyari River known as the Meet'ha Darwaaza (Sweet Gate) (Mithadar). The location of these gates correspond to the modern areas of Kharadar (Khārā Dar) and Mithadar (Mīṭhā Dar).