A newly-developed tribology model is integrated with a reduced-order heat transfer model to construct a simulation platform which is used to conduct system-level simulation of transient multi-physics loss-of-lubrication (LoL) operation of a high-speed gearbox. In the simulations, the processes of increasing gear bulk temperature and of oil depletion are transient. The former is captured by the reduced-order heat transfer model, and the latter is studied parametrically. A nominal problem is studied based on LoL tests of involute spur gears by NASA Glenn. The simulation results qualitatively capture the trend and scale of the "thermal run-away" observed in the experiments. Parametric analyses are carried out to demonstrate the capability of the simulation platform to guide design optimizations in various aspects, including gear configurations, material considerations and secondary emergency lubrication systems.