Experimental research is the most reliable means for prediction of nonlinear structural behavior and the failure mechanism under extreme dynamic loads. The primary objective of this research is to advance the current state of technology for large-scale experimental testing through the development of a multi-axis substructure testing system capable of simulating the three-dimensional continuously-varying loading schemes during extreme loading events. This state-of-the-art facility can be used for quasi-static cyclic testing or local and geographically-distributed hybrid simulation of large/full scale structures. This system also incorporates the switched and mixed load/deformation control strategy that is critical to apply simultaneously the load in the highly stiff axes while imposing deformations in other directions on the test specimen. To demonstrate the multi-directional mixed-mode testing framework, three experiments including quasi-static cyclic, local and distributed hybrid simulation tests were conducted on a seismically-excited concrete structure. The experimental results show that the complex boundary effects on the physical test specimen can be reliably simulated through the unique capabilities of this testing system.