Control panels, computers and other equipment have been targeted at the facility in Annsborough, where raw sewage from 2,100 homes in the area is treated.
NI Water said almost £100,000 has already been spent repairing damage.
The most recent attack took place on 13 January and there are fears that broken equipment could affect processes and potentially lead up to a major pollution incident.
Alec McQuillan, Head of Wastewater at NI Water, said: "These incidents have been going on for about a year and have resulted in considerable expense and disruption.
"Almost £100,000 has been spent repairing damaged equipment, introducing increased security and installing new equipment at the site.
"This area has a well-deserved reputation for the beauty of the waterways and coastline and we, as a company, view the protection of that environment as a major priority.
"It is for this reason that we are particularly concerned about the potential that these attacks have to cause a significant incident."
The company said it has been working closely with the PSNI over the attacks.
A statement from Chief Inspector Deirdre Bones said: "Those carrying out these senseless acts of vandalism are putting themselves in danger and putting the whole community at risk of a potentially serious pollution incident. I would appeal to whoever is responsible for these attacks to stop now before even more serious damage is caused."
Anyone with more information can call Newcastle Police Station on 0845 600 8000.
Meanwhile local MP Margaret Ritchie condemned those responsible.
"Those people who are causing damage at the plant are also putting the wider community at risk of a serious pollution incident and they should stop to consider the ramifications of their mindless vandalism," she said.
"I would urge anyone who may have seen anything suspicious at the plant over the weekend to come forward and help the police with their enquiries."