His father Ghulam Rasool Jatoi was a member of the Sindh Legislative Assembly twice in 1946 and again 1952, after which one unit was imposed in West Pakistan.

He held the Portfolios of Political Affairs, Ports and Shipping, Communications, Petroleum and Natural Resources, Information Technology, Railways & Telecommunications in the Federal Government headed by Prime Minister Zulfikar Ali Bhutto.

A number of political heavyweights from all over the country were brought into the National People's Party, launched under the chairmanship of Ghulam Mustafa Jatoi.

Among them were Ghulam Mustafa Khar, Haneef Ramay, Hamid Raza Gilani and Kamal Azfar.

The NPP and the PML, then headed by Muhammad Khan Junejo, along with seven other political parties, contested the 1988 elections from the platform of the Islami Jamhoori Ittehad.

Mr. Jatoi was appointed prime minister after the dismissal of the Benazir Bhutto government on corruption and incompetence charges by President Ghulam Ishaq Khan.

In the 2008 election his son Ghulam Murtaza Khan Jatoi won election in NA-211 Naushahro Feroze-I under the banner of the National Peoples Party, defeating the runner-up PPP candidate and holding the seat won in 2002 by Dr. Abdul Ghaffar Khan Jatoi under the National Alliance banner.

Ghulam Mustafa Jatoi died in London on Friday November 2009 after a protracted illness at the age of 78.