Police say the still to be identified victim, thought to be a 17-year-old boy, was found suffering stab wounds at a home in Casino around 1.30am on Saturday.
He was treated by paramedics but died at the scene.
The residence is to undergo forensic examination, while a search of the surrounding area has been conducted with help from the dog unit and local police.
The homicide squad will also assist with the case, with initial inquiries suggesting the incident was targeted.
The boy's death follows that of a 50-year-old man involved in a physical altercation at South Grafton, on the state's north coast, on Friday morning.
Police say a 64-year-old man arrested at the scene will face court charged with manslaughter.
Emergency services were called to Phoenix Close following reports of a neighbour dispute shortly after 9.30am.
On arrival, they found the man unresponsive and suffering head injuries.
He was treated by ambulance paramedics but was unable to be revived.
The accused man was expected to appear in Port Macquarie Local Court on Saturday.
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