Gri3D® is a ready-to-use platform for high-throughput and reproducible organoid culture. Here we describe its use to perform an automated drug screen of 80 anti cancer compounds on HCT-116 spheroids and patient-derived colorectal cancer (CRC) organoids. Up to 73 homogeneous microtissues are generated in a single well, and their response to treatment is assessed by high content imaging. More than 250 phenotypic metrics are extracted from each microtissue. Further analyses reveal a previously unobserved phenotype on organoids grown on Gri3D® during the administration of subtoxic levels of afuresertib. Our system allows assessment of drug effects at a single-organoid level in a fully automated high throughput screen workflow.