Prof Mkhize served in the Inter University Executive. from 1974 to 1977. Between September 1986 and March 1987, she was a visiting professor at the University of Illinois and in 1989, she was a visiting professor at the University of Mississippi.
She has served in the Academic Staff Association of the University of Zululand and was a senior lecturer at the University of Zululand from 1984 to 1990. In 1990, Prof Mkhize served in the central committee, which organised the biggest rally at the University of Zululand, celebrating the release of Nelson Mandela.
From 1990 to 1995, she was a senior lecturer and researcher at the University of the Witwatersrand. From 1995 to 1999, she served in the interim BEC of the ANC in Sandton from 1995 to 1999; and from 1999 to 2000, she served as deputy chair of the ANC?s Sandton BEC and as ANC zonal chairperson, in (Alexandra Township, Sandton and Johannesburg East).
Between 1991 and 1995, Prof Mkhize also served in the ANC BEC in Diepsloot; in the National Conflict Resolution Centre Action Committee Against Violence; in the National Women's Resource Centre; as board member of the Human Rights Foundation, and the Goldstone Commission Committee to clarifying the status of traumatised children.
From 1994 to 1995, she was a board member of the South African Prisoner's Organisation for Human Rights; and from 1995 to 2003, she was a commissioner of the Truth and Reconciliation Commission and chairperson of the Reparations and Rehabilitation Committee. From 1996 to 2004, Prof Mkhize was a member of the Peace Accord Secretariat and later trustee of the National Peace Accord Trust.
Between 2001 and 2005, Prof Mkhize was chairperson of the FAZE 2 Civil Society Organisation after the World Conference Against Racism and served as reparations officer in the President's Fund located in the Ministry of Justice.
During the period 2004 to 2008, she was chairperson of the Executive Council of the Organisation for the Prohibition of Chemical Weapons and chairperson of the Council of the University of Zululand. She also served as chairperson of Transparency International South Africa, and was vice president of the member states at the International Criminal Court at The Hague and the United Nations.
Between 2001 and 2004, Prof Mkhize was secretary of the ANC Havana City Branch. During the same period, she was the chairperson of the ANCWL, and she was elected by civil society in her residential area to serve as a health representative within the local Councillor's Committee.
Prior to her appointment as Deputy Minister, Prof Mkhize served as Ambassador of South Africa to the Netherlands from 2005 to 2008.
She was Deputy Minister of Correctional Services from May 2009, to June 2012, and the Deputy Minister of Economic Development from June 2012 until May 2014.
Prof Mkhize served as the Deputy Minister of Telecommunications and Postal Services of the Republic of South Africa; a position she was appointed to on 26 May 2014 until 30 March 2017.
Prof Hlengiwe Buhle Mkhize served as the Minister of Home Affairs of the Republic of South Africa with effect from 31 March 2017 until 17 October 2017.