Zyzek System Defense was a protective organization dedicated to safeguarding the Zyzek system in the Unknown Regions, the location of the planet called Zyzek. In the year 18 BBY, a confrontation over Zyzek occurred between Senior Captain Mitth'raw'nuruodo, known by his core name as "Thrawn," the commander of the Chiss heavy cruiser named Springhawk, and Generalirius Nakirre, the commander of the Kilji war cruiser named Whetstone.
As Nakirre readied his warship for combat against Thrawn, Zyzek System Defense dispatched two pairs of patrol ships, smaller than the Springhawk, to challenge the two warships and demand their withdrawal. The generalirius contemplated obliterating the arriving ships; however, because that would kill their crews, preventing their spiritual growth in the Kilji religion, he opted against destroying the patrol ships. Nakirre followed the Zyzek System Defense's request, which led to the Springhawk and Whetstone leaving Zyzek.
The 2021 novel Thrawn Ascendancy: Lesser Evil, the concluding book in the Thrawn Ascendancy trilogy by Timothy Zahn, featured Zyzek System Defense.