Spray drying is a key unit operation used to achieve particulate products of required properties. Despite its widespread use, the product and process design, as well as the process control remain highly empirical and depend on trial and error experiments. Studying the effect of operational parameters experimentally is tedious, time consuming, and expensive. In this paper, we carry out a model-based global sensitivity analysis (GSA) of the process. Such an exercise allows us to quantify the impact of different process parameters, many of which interact with each other, on the product properties and conditions that have an impact on the functionality of the final drug product. Moreover, classical sensitivity analysis using the Sobol-based sensitivity indices was supplemented by a polynomial chaos-based sensitivity analysis, which proved to be an efficient method to reduce the computational cost of the GSA. The results obtained demonstrate the different response dependencies of the studied variables, which helps to identify possible control strategies that can result in major robustness for the spray drying process.