LLNL’s primary mission is to assure the safety and reliability of the U.S. nuclear stockpile. In the absence of nuclear weapons testing, LLNL accomplishes its stockpile stewardship mission using experimentally anchored, predictive multi-physics simulations of weapon system performance. We have adapted this approach to other high value national security missions using a Model-Based Systems Engineering (MBSE) methodology as part of an overall Digital Engineering (DE) strategy. Predictive multi-physics simulations of unprecedented, first-of-a-kind, weapon systems serve as computational prototypes for proof of principle, engineering risk-reduction, and operational concept development activities. The experimental and computational foundations of LLNL’s MBSE capability relevant to Hypersonics are reviewed and applications to weapon systems development are discussed.