Colorectal cancer (CRC) is the second-leading cause of cancer-related deaths worldwide. Organoid models of colorectal cancer have emerged as a powerful experimental platform. However, application of large-scale approaches such as CRISPR/Cas9 screens to organoids are scant due to technical and financial barriers. Here, we develop a framework for CRISPR/Cas9-based screening in colorectal organoids by conversion to a cost-effective and scalable monolayer culture system. We apply this approach to a genetically defined organoid model of colorectal adenocarcinoma and conduct in vitro essentiality and invasion screens alongside in vivo gain of metastasis screens. We pinpoint various regulators of CRC growth and viability, including Rad54l2 and Smarcad1 as novel CRC oncogenes. We also identify Ctnna1 and Bcl2l13 as bona fide metastasis-specific suppressors which do not confer any selective advantage in primary tumors. CTNNA1 loss promotes cell invasion and migration, and BCL2L13 loss promotes anchorage-independent survival and non-cell-autonomous changes to macrophage polarization. Additionally, we define an APC-regulated GSK3 phosphorylation event on SETD8, a histone methyltransferase that scored as a hit in our in vitro essentiality screen. We find that phosphorylation of SETD8 Thr138 is a tumor suppressive event in multiple models of colorectal cancer and induces a distinct transcriptional landscape in colorectal cancer organoids. This study demonstrates proof-of-principle that high-content genetic screening can be performed in tumor-organoid models and identifies novel regulators of tumorigenesis and metastasis.