to President Bashar al-Assad are stationed when it was struck by the blast, the Syrian Observatory for Human Rights said.
"Twenty-one people were killed in the Nawa area (of Daraa), among them four children and six women, in a blast that detonated as their vehicle went past Tal al-Jumua," the Britain-based Observatory said.
Activists have accused regime troops of planting the explosives, the watchdog said.
A battalion of troops loyal to Assad "is positioned there, and is under siege by rebel forces", it added.
Daraa is the cradle of the uprising that broke out against Assad in March 2011.
The Observatory says more than 115,000 people have been killed in the war that erupted after Assad's troops unleashed a brutal crackdown against protesters calling for political change.
Of those who have died, 41,533 were civilians, including 6,087 children and 4,079 women, according to the group.
Rebels fighting Assad's troops have made significant progress in recent months in Daraa, which is strategically located on the border with Jordan and near Damascus province.
The latest civilian deaths come as the United States presses efforts to persuade a key Syrian opposition group to drop its refusal to join planned talks in Geneva.
A stalled peace initiative dubbed Geneva 2 has been proposed by Washington and Moscow aimed at bringing rebel and regime representatives to the negotiating table.
But the Syrian National Council (SNC), which is the biggest bloc within the Syrian opposition coalition, said at the weekend it would not join the talks planned for next month and would quit the umbrella group if it attends.
The SNC cited as its reasons for snubbing the talks the ongoing suffering of Syrians on the ground. It stressed it would not enter any negotiations before the fall of Assad's regime.
The US, which backs the opposition in Syria's war, has urged the SNC to drop its refusal to join the talks, saying its participation is essential.
"There have been many ups and downs in this process. And that's not unexpected given how challenging the situation is on the ground," State Department spokeswoman Jen Psaki said.
"But we continue to press for the opposition to have a representative body at the Geneva conference, " she told reporters in Washington on Tuesday.
The so-called Geneva II peace conference was first talked of in May but has been postponed several times due to internal wrangling among the opposition and a dispute on which countries should have a place at the negotiating table.
The situation has been exacerbated by a chemical weapons attack on Damascus suburbs in August which left hundreds dead.
Washington led other world powers in accusing Assad's regime of using the prohibited weapons and threatened military strikes against Assad's regime.
While denying regime troops were behind the attack, Damascus agreed to allow international experts to destroy its massive chemical arsenal as it raced to avert a strike by US forces.
Acting under a subsequent UN Security Council resolution, the Organisation for the Prohibition of Chemical Weapons has since begun destroying the weapons in an operation expected to last until mid-2014.
The UN Resolution 2118 also called for peace talks, but the opposition has criticised it for failing to guarantee justice for the victims of Syria's war.
Elsewhere in Syria on Wednesday, fierce clashes raged in the northeastern province of Hasake, pitting Kurdish fighters against jihadists, the Observatory said.
At least 10 al Qaeda-linked fighters were killed, it added.
Clashes have raged in majority Kurdish areas for months, as the jihadist Islamic State of Iraq and the Levant (ISIL) has sought to expel the Committees for the Protection of the Kurdish People (YPG) from areas under their control.