At about 3.30pm on Saturday, a white Toyota and a red Subaru collided on the New England Highway near Wallabadah, south of Tamworth.
The Subaru was forced off the highway and down a small gully, and the Toyota rolled on the highway.
The male driver of the Subaru and his female passenger died at the scene. They have yet to be formally identified but are believed to be aged in their 60s.
The 69-year-old male driver of the Toyota and the 67-year-old female passenger were treated at the scene by Ambulance paramedics before being taken to Tamworth Hospital for treatment to suspected minor injuries.
Police from Oxley Local Area Command are investigating the crash.
The New England Highway was closed in both directions for six hours as Northern Tablelands Crash Investigation Unit conducted their inquiries.
Anyone who witnessed the crash, and has not yet spoken with police, is encouraged to contact Crime Stoppers.
A report will be prepared for the information of the Coroner.