During the negotiations to end apartheid, he worked at Shell House as the head of the ANC's internal department of economic planning from 1991 to 1994.

He became Mandela's Minister of Finance in a cabinet reshuffle in April 1996 and remained in that office for the next 13 years, serving throughout the terms of Presidents Thabo Mbeki and Kgalema Motlanthe.

[1] He later said that "politics came to me" when his primary school class was halved by the implementation of the Bantu Education Act,[5] and he was active in local civic organisations as a teenager.

[7] In 1996, Mark Gevisser described him as having been a "solid workhorse of the UDF"; in Gevisser's description: He's the one who, in the rough-and-tumble world of Cape Flats politics, once even punched out current Western Cape Nat MEC Peter Marais at a public meeting; the long-haired biker who used to cruise around in tight Lee jeans, studded shoes and leather jacket.

[1] He was detained for the first time on 22 October 1985, held under the Internal Security Act, and released a month later under a stringent banning order.

[10] Also during this period in 1989, Manuel returned briefly to the private sector as a policy manager for the Mobil Foundation in Cape Town.

[10] However, he was soon promoted: the national ANC held its first conference inside South Africa in Durban in July 1991 and Manuel was elected to the party's top executive organ, the National Executive Committee; by number of votes received, he was ranked 19th of the committee's 50 members, receiving support across 64 per cent of all ballots cast.

[13] In the aftermath of the conference, he was recruited full-time to the ANC's headquarters at Shell House, where he was head of the party's nascent department of economic planning.

[2] According to Gevisser, during this period, Manuel "played a critical role in guiding the ANC away from its traditional adherence to centralised planning and towards the market economy it was to espouse".

[1] He said that his priorities would include aligning trade policy and industrial strategy; seizing opportunities "to open up our domestic market to international competition", thus reversing the isolation of the apartheid era; and encouraging long-term investments in human and other capital.

[20] On 28 March 1996, President Mandela announced that Chris Liebenberg had resigned as the Minister of Finance and would be replaced by Manuel, with Gill Marcus as his deputy.

[14] Soon into his tenure, on 14 June 1996, he announced the government's new Growth, Employment and Redistribution (GEAR) programme, which was viewed as its critics as a marked rightward shift from the Reconstruction and Development Programme; GEAR targeted the reduction of the budget deficit to three per cent, more rapid tariff reductions, constraints on the public sector wage bill, and other so-called market-friendly measures.

[26] Even those broadly complimentary of Manuel's tenure as Minister of Finance noted that his ministry had failed to address structural economic problems, particularly poverty, unemployment, and inequality.

[27][14] Responding to this complaint in April 2014, Manuel said: No, I don't think finance ministers can take responsibility for all of those things... You see, one of the misplaced issues regarding economic discourse in this country is that there's this belief that macroeconomics is everything.

[14]Long regarded as a pragmatist,[9] Manuel said in 2013 that he still had little technical knowledge of economics, but "I knew that if I set this thing up where people can come with the numbers, and I ask the questions based on life experience and understanding and broad political objectives, then it will work.

[31] At the December 2007 elective congress, the 52nd National Conference in Polokwane, he was one of only a handful of Mbeki's cabinet who was re-elected, in Manuel's case ranked 57th of 80.

Richard Calland said that, amid uncertainty about the consequences of the upset, "the anxiety is distilled into one question: Will Zuma keep Trevor Manuel as minister of finance?

In August 2015, the Business Day published a document which implicated Manuel in an elaborate conspiracy codenamed Project Spider Web, apparently hatched during the post-apartheid transition with the aim of maintaining the influence of the white establishment over the National Treasury and South African economic policy.

[42][45][46][47] In October 2016, the Citizen reported, based on access to a leaked document, that Manuel had approved a R100-million modernisation contract that had been awarded at the South African Revenue Service (SARS) without a proper bidding process.

[56] However, early in his tenure, opposition parties criticised him for using R1.2 million in public money to purchase a luxury BMW as a ministerial vehicle.

Cosatu called for it to be withdrawn, with Zwelinzima Vavi warning that Manuel would become a de facto "imperial" prime minister and would marginalise other ministries and the Tripartite Alliance.

[61][62] Nonetheless, when President Zuma announced the composition of the inaugural 24-member National Planning Commission on 30 April 2010, Manuel was appointed as chairperson, with businessman Cyril Ramaphosa as his deputy.

The choice facing us is very clear: do we stand behind the humane and generous values of Minister Manuel, or do we, by staying silent, lend our support to the mischievous and dangerous notions of Mr Manyi.

Ngobeni accused Manuel of being "a gangster of the worst kind", of acting as though he was "the king of Coloured people", and of seeking to undermine President Zuma and his cabinet through his "cowardly, unwarranted and racist attacks on Manyi".

He told the house that, "At some point serving leadership must give way so that new blood, fired up with life-changing ideas, can take society to a higher level of development".

In April 2016, in an interview with Soweto TV, he said that it would be "in all of our interests that the president actually steps aside",[85] and he was critical of Zuma's administration during his testimony to the Zondo Commission in February 2019.

[89] The EFF alleged in a statement that Manuel presided over a "nepotistic" and "corrupt" process, remarks later found to be defamatory by the Pretoria High Court.

[93] In late 2024, United Nations Secretary-General António Guterres appointed Manuel to group of experts to promote actionable policy solutions and galvanize political and public support required to resolve the developing world’s debt crisis, chaired by Mahmoud Mohieldin.

[95] The World Economic Forum selected Manuel as a Global Leader for Tomorrow in 1994,[19] and he was Euromoney's African Finance Minister of the Year in 1997.