Due to the growing demand for robust autonomous systems, automating maintenance and fault mitigation activities has become essential. If an unexpected fault occurs during the travel, the system should be able to manage that fault autonomously and continue its mission. Thus, a robust fault mitigation system is needed that can quickly reconfigure itself in an optimal way. This paper presents a novel digital twin-based fault mitigation strategy that uses hierarchical control architecture. Here, a computationally efficient high-fidelity hybrid engine model is developed to simulate actual engine behavior. This hybrid engine model includes a neural network model representing the cylinder combustion process and well-studied physics-based analytical equations describing the remaining subsystems. This architecture uses a feedback controller on top of the control calibration map, generated offline using the hybrid model, to mitigate faults and modeling errors. The fault mitigation strategies are calibrated and validated through model-in-loop (MIL) and hardware-in-loop (HIL) simulations for various operating points using the Navistar 7.6 liters six-cylinder engine. The effectiveness of the proposed architecture in handling injector nozzle clogging, intake manifold leaks, and pressure shift faults is illustrated. The results demonstrate that the proposed architecture can completely overcome faults and maintain the desired torque in a few seconds. Moreover, the average accuracy of 96% is observed for the engine model compared to experimental data. It is anticipated that the proposed end-to-end architecture will be easily deployable on unmanned marine vessels and can be extended to accommodate other component faults.