Four other people were taken to the hospital.
Myrtle Beach Police Cpt. J.M. Kerns told local media that a minivan and a Mercedes sedan collided on U.S. 17 around 8 p.m.
Horry County Coroner Robert Edge said the girls were in the backseat of the minivan.
WPDE-TV reports Edge has identified the girls as Skyler Emore, 9, and Dakota Shepherd, 11. They were pronounced dead at the scene of the crash from internal injuries, Edge said.
The South Carolina Highway Patrol is investigating the wreck.
Myrtle Beach Online reports troopers said the minivan was trying to turn into a private property parking lot across from Pirateland Family Camping Resort entrance when it was hit.
Cpl. Hannah Wimberly with the S.C. Highway Patrol said after the Mercedes struck the van, it then struck a car parked in that parking lot.
The driver of the Mercedes was identified as Neil Joseph DeJean, 47, of Duson, La. He's charged with two counts of reckless homicide caused by injury from a vehicle and one count of open alcohol container.