Abstract Glioblastoma (GBM) lethality arises from aggressive invasion and diffuse infiltration of brain tissue. Conventional GBM preclinical models often fail to predict clinical therapeutic efficacy because they do not recapitulate the pathological extracellular matrix (ECM) cues that drive tumor invasion. Here, we present an ECM mimetic 3D platform using a fibrin scaffold to recapitulate the hemorrhagic, pro-thrombotic tumor microenvironment characteristic of high-grade gliomas. This fibrin scaffold induces a pro-invasive phenotype in GBM spheroids by upregulating proliferation/cell cycle- ( MYC, FOXOM1, CCND1 ) and invasion-associated-( CTSS, FOXM1, CCND1 ) genes. Traditional cell morphology quantification methods (e.g., circularity) distil complex shapes into singular metrics and cannot capture the nuances of invasion. To address this limitation, we have applied a deep-learning segmentation pipeline (MARS-Net) and high-content morphodynamic descriptors. By using the Preserving Heterogeneity (PHet) algorithm, the 3D platform accurately classifies invasiveness levels and captures the invasion-inhibitory effects of potential repurposable drug candidates. We demonstrate that our model can predict a spheroid’s long-term invasive fate with high accuracy using only partial image sets from early time-points, rather than the complete time-course images. Our work presents an in vivo -like, scalable 3D platform integrated with a quantitative high-throughput pipeline to elucidate GBM invasion mechanisms and to evaluate anti-invasive compounds.