The Islamic State group said it was behind the bomb attack on Al-Diyabiyah, a town serving as one of the gateways for pilgrims from around the world who visit the Shiite holy site.
Another 20 people were wounded, state news agency SANA reported.
The Syrian Observatory for Human Rights put the death toll at eight and had no immediate word on whether civilians were among the dead.
The shrine contains the grave of Zeinab, a venerated granddaughter of the Prophet Mohammed, and is known for its glistening golden onion-shaped dome.
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A guard at the checkpoint told AFP his bomb detector began beeping when a suspicious pickup truck pulled up.
"We stopped the car at the checkpoint... When we began doing a manual search, they detonated the car. My colleagues were killed," he said.
The windows of a small hotel across from the checkpoint were blown in by the blast.
The hotel is mostly occupied by displaced people from Fuaa and Kafraya, two Shiite-majority towns in northwest Syria that are under siege by Islamist rebels.
The area around the shrine, which is heavily secured with regime checkpoints hundreds of metres (yards) away to prevent vehicles from approaching, has been hit by Sunni extremists from IS several times this year.
In online media, IS said today's attack killed or wounded more than 48 people.
A string of IS bombings near the shrine in February left 134 people dead, most of them civilians, according to the Observatory.
Lebanese Shiite militant group Hezbollah cited the threat to Sayyida Zeinab as a principal reason for its intervention in the civil war on the side of President Bashar al-Assad.
More than 270,000 people have been killed and millions more been forced to flee their homes since the conflict erupted in 2011.