Titanium matrix composites (TMCs) are being evaluated as structural materials for elevated temperature applications in future generation hypersonic vehicles. In such applications, TMC components are subjected to complex thermomechanical loading profiles at various elevated temperatures. Therefore, thermomechanical fatigue (TMF) testing, using a simulated mission profile, is essential for evaluation and development of life prediction methodologies. The objective of the research presented in this paper was to evaluate the TMF response of the [0/90]2s SCS-6/TIMETAL-21S subjected to a generic hypersonic flight profile and its portions with a temperature ranging from −130 to 816°C. It was found that the composite modulus, prior to rapid degradation, had consistent values for all the profiles tested. The accumulated minimum strain was also found to be the same for all the profiles tested. A micromechanics-based analysis was used to predict the stress-strain response of the laminate and of the constituents in each ply during thermomechanical loading conditions by using only constituent properties as input. The fiber was modeled as elastic with transverse orthotropic and temperature-dependent properties. The matrix was modeled using a thermoviscoplastic constitutive relationship. In the analysis, the composite modulus degradation was assumed to result from matrix cracking and was modeled by reducing the matrix modulus. Fatigue lives of the composite subjected to the complex generic hypersonic flight profiles were well correlated using the predicted stress in 0° fibers.