Human brain development depends on tightly coordinated gene-regulatory programs and the emergence of complex tissue architectures, making functional studies difficult in conventional models. To overcome this challenge, we integrated CRISPR-based screening with stem cell–derived cerebral organoids to create ORIGUMI (ORganoid Interrogation by Guides and Unique Molecular Identifiers), a high-throughput knockout platform that uses genetic barcoding to track gene function in heterogeneous 3D tissues. Guided by neuro-specific whole-genome screens in Drosophila, we selected 129 poorly characterised human genes and demonstrated that ORIGUMI could reliably detect both expected depleted (e.g., SOX2) and enriched (e.g., SUFU) controls, as well as identify new developmental regulators. We validated major hits using individual CRISPR knockouts assessed by organoid growth and by longitudinal imaging of fluorescently tagged mutant cells. Among newly identified regulators, we uncovered a role for FBXW11, a ubiquitin ligase that limits organoid expansion. FBXW11 loss increased radial glial populations, impaired neuronal maturation, and altered WNT signalling through aberrant β-catenin regulation. These findings demonstrate that ORIGUMI enables robust, time-resolved genetic interrogation in complex human tissues and provides a scalable framework for dissecting neurodevelopmental processes and modelling disorders such as autism and schizophrenia.