Traditional fleet operations and technologies are not adequately suited to counter the growing threat to undersea infrastructure from autonomous undersea systems. A cost-effective unmanned and manned system of systems is required to provide defense of this seabed infrastructure. This paper proposes possible system architectures to defend against this emerging threat to include passive barriers and active defense systems. The effectiveness of those candidate systems is evaluated through multiple agent-based modeling simulations of UUV versus UUV engagements. Analysis resulted in two major findings. First, point defense of critical assets is more effective than barrier defense. Second, system design must focus on minimizing the time required to effectively engage and neutralize threats, either through improvement to defensive UUV speed or investment in more UUV docking stations and sensor arrays. Cost analysis suggests that acquisition and operations cost of the recommended defensive system is less than the projected financial impact of a successful attack.