The proposal was adopted during a chaotic city council meeting, with the ANC – virulently opposed to the motion – locked out of the venue.
Cape Town is under the control of the DA.
The proposal to rename a 5km section of the highway, which was previously called Table Bay Boulevard, after De Klerk was put forward by a group of 27 signatories.
The signatories include fellow Nobel Peace laureate Archbishop Desmond Tutu and DA leader Helen Zille.
But the move has been fiercely opposed by the left, including the ANC, South African Communist Party and trade union federation Cosatu.
“This move is an affront to the memory of all those who bravely fought and were brutally murdered and even hanged by the apartheid regime,” the SACP said earlier this month.
Cosatu called De Klerk “an accident of history” who was “forced to negotiate with the ANC to ensure that the big businesses did not lose what they stole in a bloody civil war”.
Yesterday, ANC councillors disrupted the first city council sitting of the year until the DA majority chose to change venues.
The DA locked the ANC out of the new venue – and out of the voting process.
The Cape Town mayor’s office said the proposal had received “overwhelming support” from the public.
De Klerk’s foundation had previously said he was “honoured and touched” by the proposal. De Klerk was South Africa’s last head of state under apartheid.