A medical doctor by training, Ramokgopa began her political career in the provincial government of Gauteng.
[5] In 2003, she caused mild controversy by insisting that the Ga-Rankuwa Hospital (where she previously worked) should be renamed after a local doctor and activist named George Mukhari; the opposition Democratic Alliance claimed that Ramokgopa had not consulted the community about the decision and that she was motivated by her personal friendship with the Mukhari family.
[17] In February 2017, Ramokgopa was returned to her earlier position as Gauteng MEC for Health, this time by Premier David Makhura.
[4] Upon taking office, Ramokgopa promised of the tragedy that her department would "reflect on this experience, as difficult as it is, and find ways to restore the confidence of our people in our health system".
[18] In May 2010, while still Tshwane Mayor, Ramokgopa was elected Deputy Provincial Chairperson of the ANC in Gauteng, deputising Paul Mashatile.
[7][26] In October 2022, she was listed as the preferred Treasurer-General on a slate of candidates endorsed and circulated by figures in the party's pro-Ramaphosa faction.
[28][29][30][31] During the nominations phase, however, local party branches were not sufficiently supportive of her campaign for her to appear on the provisional ballot.