Real-time hybrid simulation is an efficient and cost-effective dynamic testing technique for performance evaluation of structural systems subjected to earthquake loading with rate-dependent behavior. A loading assembly with multiple actuators is required to impose realistic boundary conditions on physical specimens. However, such a testing system is expected to exhibit significant dynamic coupling of the actuators and suffer from time lags that are associated with the dynamics of the servo-hydraulic system, as well as control-structure interaction (CSI). One approach to reducing experimental errors considers a multi-input, multi-output (MIMO) controller design, yielding accurate reference tracking and noise rejection. In this paper, a framework for multi-axial real-time hybrid simulation (maRTHS) testing is presented. The methodology employs a real-time feedback-feedforward controller for multiple actuators commanded in Cartesian coordinates. Kinematic transformations between actuator space and Cartesian space are derived for all six-degrees-offreedom of the moving platform. Then, a frequency domain identification technique is used to develop an accurate MIMO transfer function of the system. Further, a Cartesian-domain model-based feedforward-feedback controller is implemented for time lag compensation and to increase the robustness of the reference tracking for given model uncertainty. The framework is implemented using the 1/5th-scale Load and Boundary Condition Box (LBCB) located at the University of Illinois at Urbana- Champaign. To demonstrate the efficacy of the proposed methodology, a single-story frame subjected to earthquake loading is tested. One of the columns in the frame is represented physically in the laboratory as a cantilevered steel column. For realtime execution, the numerical substructure, kinematic transformations, and controllers are implemented on a digital signal processor. Results show excellent performance of the maRTHS framework when six-degrees-of-freedom are controlled at the interface between substructures.