<p>Due to late diagnosis, high molecular diversity, and limited response to therapeutic intervention, gastrointestinal (GI) cancers result in a considerable number of cancer-related deaths. Classic clinicopathological classification and single omics analysis fail to adequately convey the extensive biological complexity related to progression of disease, developed therapy resistance and recurrence of the disease. As a result, the recent introduction of integrated multi-omics including genomics, epigenomics, transcriptomics, proteomics, metabolomics and spatial profiling as well as the emerging use of liquid biopsy is substantially reshaping our understanding of and clinical approach to GI cancers. This review summarizes developments to illustrate how the incorporation of multi-omics across GI tumors offers a better understanding of GI cancers and providing more precise and less costly ways to detect disease earlier, develop molecular subtypes of the tumors with greater accuracy for the purpose of developing an individualized risk stratification system for patients. Furthermore, the article will discuss the growing use of minimal residual disease monitoring and the use of ctDNA in guiding a patient’s post-operative surveillance and treatment decision-making process. In addition, this review focuses on the value of using multi-omics-based knowledge of a tumor’s microenvironment to better predict how effective immunotherapy will be and support the effective combination of drugs for the treatment of GI cancers and how targeted therapy will broaden the clinical practice landscape for developing therapeutics containing new vulnerable targets. Finally, the review provides an overview of current barriers to the implementation of multi-omics and point out to future opportunities. Collectively, emerging omics data suggest a meaningful shift toward precision oncology in gastrointestinal cancers, though widespread clinical implementation remains an active area of investigation.</p>