Colorectal cancer (CRC), a leading cause of cancer-related mortality worldwide, is a multifactorial disease influenced by genetic, epigenetic, and environmental factors, including the gut microbiota. The gut microbiota, a complex ecosystem of microorganisms, plays a pivotal role in CRC pathogenesis, progression, and response to therapy. Dysbiosis—imbalances in the microbiome—has been linked to tumor initiation and immune evasion, highlighting its role as a potential therapeutic target. This chapter explores the emerging significance of microbiome-targeting strategies in CRC management. These approaches, including probiotics, prebiotics, synbiotics, dietary modifications, and fecal microbiota transplantation (FMT), aim to restore microbial homeostasis and improve treatment outcomes. Additionally, the gut microbiome influences the efficacy and side effects of chemotherapy and immunotherapy, with specific microbial profiles correlating with treatment response. Postbiotics, bioactive compounds produced by beneficial microbes, further enhance therapeutic potential by modulating the immune system and exerting anti-inflammatory effects. Personalized microbiome modulation, tailored to an individual’s microbial profile, offers a promising avenue for optimizing CRC treatments. Dietary interventions, particularly those rich in fiber, polyphenols, and omega-3 fatty acids, also demonstrate significant potential in enhancing gut health and mitigating CRC progression. Future research should focus on integrating microbiome data into personalized treatment regimens, optimizing delivery mechanisms, and understanding geographical and demographic variations in microbiome composition. By advancing microbiome-targeting strategies, this work underscores the potential of leveraging gut microbiota and postbiotics to revolutionize CRC prevention, treatment, and prognosis, providing a foundation for personalized medicine in oncology.