The C-130 Hercules took off at 11.58am and is due to touch down in Mthatha in the afternoon.
The convey carrying Mandela’s body will then drive through the streets of Mthatha before being taken to Qunu, about 31km away, where he spent much of his childhood, for Sunday’s state funeral.
Earlier, Nelson Mandela’s widow Graca Machel wept when she was handed the neatly folded African National Congress flag that had been draped over the coffin during a special ANC tribute ceremony at the airbase.
Frail-looking struggle heroes and long-time friends of Mandela, Ahmed Kathrada and Andrew Mlangeni, were among the pallbearers and due to travel with the coffin.
Senior family members were expected to accompany the body during the flight.
Speaking in Qunu earlier, AmaHegebe chief Phathekile Holomisa said that before the plane left and throughout the journey, an elder or senior male family member would talk to the body and keep it informed of the progress of the journey.
The person would address Mandela as if he was still alive, Holomisa explained.
“This is so because his spirit lives.”
Mandela, who was South Africa’s first democratically-elected president, died at his home in Houghton, Johannesburg, last Thursday, at the age of 95.