According to reports, two buses collided on the R61 between Cradock and Graaf-Reinet.
One of the buses was transporting school children to a school event in Graaf-Reinet, while the other was carrying passengers travelling from Cape Town to Mthatha.
Two schoolchildren were among the 18 killed. Fourteen people were also seriously injured.
"Our thoughts and prayers are with the families of those who lost their loved ones in this tragedy. We also wish those injured a speedy recovery so that they can reunite with their families at home.
"Although these collisions appear to be taking place repeatedly leading to many deaths, we must not lose our collective sense of weeping. Even the death of one South African on our roads is unacceptable and painful, even more so these numbers of our people including children that we now appear to lose each week," Zuma said.
He called on law enforcement agencies to conduct the necessary investigations and ensure that negligence on anyone's part is punished to the full extent of the law.
