Roughly two months of its independence after the departure of the subcontinent by Great Britain, the United States established relations with Pakistan on 20 October 1947.

This is due in part to several large U.S. government regional centers housed within the consulate, which provide support in the areas of security, construction, and financial matters to a number of other U.S Diplomatic posts located throughout Asia.

Due to security reasons US government purchased 20 acres of land from the Karachi Port Trust in 2005 and ground breaking took place in May 2008.

After two years of construction work consulate shifted to the bigger place located at New TPX Area, Mai Kolachi Road.

[8] On the morning of June 14, 2002, a truck with a fertilizer bomb driven by a suicide bomber was detonated outside the United States Consulate in Karachi, Pakistan.

The police investigated the van and discovered a large blue tank filled with nearly 200 gallons of liquid explosives hooked up to a timer and two detonators.

[12] On March 2, 2006, a suicide car bomb killed four people and injured thirty outside the Marriott Hotel in Karachi, which is about 20 yards from the consulate.