The current therapeutic landscape of microsatellite-stable colorectal cancer (MSS-CRC) is deficient due to the paucity of driver mutations and diminished immune-cell responses. An emerging strategy to elucidate novel druggable targets involves characterising the MSS-CRC ‘surfaceome’, as the plasma membrane is a crucial and therapeutically accessible interface. Here, we performed extracellular biotinylation of intact patient-derived MSS-CRC organoids and quantitative proteomics on affinity-enriched organoid surface proteins, comparing healthy colon epithelium to primary and metastatic MSS-CRC. To discern potential cell-surface targets, we then established a robust and stringent filtering workflow to remove non-membranous proteins that co-isolate through interactions with plasma membrane proteins. This involved the integration of various cell surface-related gene ontology terms, protein subcellular localization information and the use of reviewed databases such as SURFY and TMHMM 2.0. Subsequently, we employed label-free quantitative (LFQ) followed by statistical and bioinformatics analyses, to refine our list of putative MSS-CRC membrane targets. Based on a total of 498 high-confidence plasma membrane proteins identified, we detected high levels of established markers PLAUR, EPCAM, FGFR1, ABCB1 and CDH17 in advanced CRC, and shortlisted 12 novel targets including DPEP1, NECTIN1, MPZL1 and SLC7A6 for further validation and therapeutic development. In this rich and clinically relevant dataset, we also uncover a large number of new MSS-CRC prognostic markers that may guide clinical staging and disease stratification in a multi-biomarker panel setting. With these, we aim to advance therapeutic strategies for MSS-CRC, which still lack effective targeted therapies, using an empirical biochemical approach. The success achieved here could be directly applied to study other forms of solid tumours, and tumour subtypes.