The cases were reported in Wau city which is the capital of Western Bahr el-Ghazal State.
Health Minister Yolanda Awel Deng urged the public to remain calm.
Hepatitis E is a liver infection caused by the hepatitis virus found in the stools of infected persons and in infected water. Symptoms include yellowing of the skin, abdominal pain, mild fever and loss of appetite.
Deng urged citizens to observe all precautionary measures, including washing their hands with soap, using latrines and maintaining a clean environment.
The disease currently has a fatality rate of 5.5% with males accounting for 73.6% of all reported cases, the health ministry said.
Outbreaks of hepatitis E have been seen in South Sudan since 2015, due to appalling living conditions, including inadequate water, sanitation, and hygiene.
South Sudan has experienced extreme flooding since 2020 which brings a sanitation problem and disease outbreaks.
Nearly a quarter of South Sudan's population has been affected by years of unprecedented flooding, according to a report Tuesday by the U.N. Development Program and the government's relief and rehabilitation commission.
Four straight years of flooding have impacted more than 2.6 million people across the world's newest nation, the report said.
Some information in this report came from Agence France-Presse