Colorectal cancer (CRC) is a leading cause of cancer related death worldwide. The lack of reliable diagnostic and prognostic biomarkers, render patients mostly detected at a late stage especially as current detection tests have very low uptake (fecal immunochemical test (FIT)/fecal occult blood test (FOBT)). Despite the high compliance of routine blood test, there is specific biomarkers to differentiate the cancer stages. Therefore, this study aims to identify diagnostic signatures for early stages of CRC in plasma and immune cells, using a multi-omics approach. The study used a unique set of matched plasma and PBMCs of 61 samples from the Victoria Cancer Biobank, 12 samples for each stage (CRC I to CRC IV) and 13 healthy controls. We quantified and analysed the kynurenine pathway (KP) metabolites and plasma protein using analytical chemistry techniques and SWATH mass spectrometry respectively while immune cells were profiled using mass cytometry. As compared to healthy control, we observed high levels of kynurenine at all CRC stages, and this suggests high IDO1 activity by CRC cells. Moreover, stage IV CRC patients have the lowest level of 3-hydroxyanthranilic acid (3HAA) and anthranilic acid. Interesting, the level of 3HAA was observed to be higher in stage IV. Proteomics analysis revealed that serum amyloid A1, galectin-3-banding protein were upregulated in stage I CRC while leucine-rich alpha-2-glycoprotein was upregulated in stage II CRC. Mass cytometry analysis revealed that higher proportion of CD4+ T cells expressing CCR4 and CXCR3 in late CRC patients as compared to early stage CRC patients. Elevated Indole 2,3 dioxygenase 1 activity in CRC patients indicates an increase in inflammation and perhaps suppressing immune surveillance for cancer survival. The upregulated SAA1 and LRG1 elevation have also been demonstrated by previous studies in early CRC detection. Our findings revealed that regulation of plasma KP metabolites and proteins, and immune cells are unique between early- and late-stage CRC. Hence, this suggest the above parameters can be used as an accurate biomarker for diagnosis and discrimination of CRC stages.