The discovery of new structural materials is slow, costly and limited, particularly for applications in extreme conditions that are challenging to mimic for characterization of properties. To address this challenge with a focus on high temperature applications, we are developing a framework to discover new structural refractories with mission-specific properties to enable enhanced capabilities in applications such as hypersonic flight. Powder directed energy deposition is used to explore the combined effects of varied composition (Nb-Vi-Ti alloy space) and process parameters. This is informed by computational fluid dynamic pre-screening simulations to guide determination of a reduced range of process parameters. Custom-designed mechanical test specimens are then fabricated across a range of compositions and process parameters in a combinatorial fashion. These specimens are then autonomously characterized using a newly developed high throughput, robotic mechanical screening approach across ambient and elevated temperatures. The data are then fed into a Bayesian optimization framework, which recommends compositions and process parameters for future evaluation. This approach has potential to rapidly accelerate structural alloy development for high temperature applications.