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Globally, colon cancer remains one of the leading causes of mortality. Multidrug resistance, systemic toxicity, and poor tumor selectivity significantly limit conventional chemotherapy. This review highlights the need for localized therapy to increase efficacy and minimize systemic side effects. Colon-targeted drug delivery systems (CDDS) are designed and developed to overcome these challenges. Both natural and synthetic polysaccharides act as carriers in CDDS because of their biodegradability, biocompatibility, pH- and enzyme-responsiveness, and mucoadhesive properties. Polysaccharides such as chitosan, dextran, pectin, alginate, and hyaluronic acid have been formulated into nanoparticles, microparticles, and hydrogels, enabling controlled and site-specific delivery. These carriers deliver chemotherapeutics, nucleic acids, and immunotherapeutics, as well as theranostic agents that combine imaging and therapy. Preclinical evidence demonstrates significant translational potential for polysaccharide-based CDDS. However, clinical trials remain limited, which highlights the gap between laboratory findings and clinical applications. Major challenges in colon-targeted drug delivery include variability in polysaccharide sources and quality, difficulties in large-scale manufacturing, and regulatory challenges. Addressing these challenges will be essential to move towards commercialization and clinical adoption. Personalized therapy through microbiome profiling, integration with nanotechnology and bioinformatics, and smart, biosensor-responsive carriers will be the focus going forward. Polysaccharide-based CDDS provide safer, more effective, and more personalized treatment with continued research to optimize delivery and overcome existing limitations.