Direct measurement of elastic constants for thin films is still far from routine and poses significant technical and analytical challenges compared to bulk materials. Ab initio Density Functional Theory calculations offer theoretical input, however, discrepancies between model systems and real-world properties persist, primarily due to a lack of available experimental data for newly emerging material systems. Moreover, computationally affordable models are typically limited to defect-free single crystals, omitting microstructural effects that strongly influence the material’s behavior. This study addresses this gap by proposing a novel experimental approach to measure direction-dependent elastic constants, combining synchrotron microdiffraction and micropillar compression, testing a polycrystalline face-centered cubic TiN0.8B0.2 thin film, where linear elastic failure prevails. We have established an advanced in-situ testing environment to continuously record the load–displacement of the indenter while simultaneously collecting the material’s deformation response to uniform uniaxial compression. This dynamic approach allows the evaluation of the orientation-dependent elastic strain components and the macroscopic uniaxial compressive stresses, each over time, enabling a differential analysis to assess the elastic and X-ray elastic constants. The excellent agreement between experimental and ab initio data solidifies the here-proposed robust method for direct elastic constant measurements, which is crucial for advancements in thin film material testing.