The move comes days after a high court judge suggested that Mr Mbeki may have interfered in a corruption case against his rival, ANC leader Jacob Zuma.
But during his address, Mr Mbeki made an impassioned defence of his position.
There had been no effort at all to meddle with the judicial process, he said. And Mr Mbeki dismissed any suggestion he had been trying to shape the judgement for his own political ends.
The BBC's Karen Allen, in Johannesburg, said this was a very measured and reflective speech.
Mr Mbeki began by saying that the ANC would decide the date of his leaving.
"I have been a loyal member of the African National Congress for 52 years. I remain a member of the ANC, and therefore respect its decisions," he said.
This was a very clear signal that he like so many others is keen to make the transition as smooth as possible, our correspondent says.
Mr Mbeki, who succeeded Nelson Mandela as president in 1999, thanked the nation and his party, the ANC, for giving him the opportunity to serve in public office.
Thabo Mbeki's political career
He went on to list some of his achievements, notably the country's solid economic growth.
He said there was still much to be done in South Africa, and he urged the incoming leadership to continue to combat poverty and social injustice.
"Trying times need courage and resilience. Our strength as a people is not tested during the best of times… For South Africa to succeed there is more work to be done and I trust that we will continue to strive to act in unity," he said.
Parliament is likely to meet in the coming days to formalise his resignation, and select a caretaker leader.
Mr Mbeki became leader of South Africa in 1999 and won a second term in 2004.
Perhaps his biggest policy success has been South Africa's rapid economic growth since the end of apartheid and the rise of a black middle class - but to the anger of many, wealth is more unevenly distributed than ever before.
He has failed to convince the trade unions and the poorest South Africans that the government has acted in their interest - providing space for Mr Zuma to mobilise a powerful constituency.
Domestically, his government's handling of the HIV/Aids crisis and failure to stem violent crime in the country also weakened his hand.
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