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Simple Summary: Research increasingly shows that bacteria, the largest part of the gut microbiome, may play a significant role in cancer. These microorganisms produce metabolites that can travel through the body and interact with host cells via microbial metabolite receptors, potentially affecting cancer development. This study investigates the involvement of these receptors in human cells across twenty-three types of cancer. By analyzing data from both cancer cell lines and human tumor samples, we examined how these interactions may impact key cancer-related processes, such as immune response, tumor growth, and spread. Notably, we identified several receptors that are consistently altered in cancer, which might serve as helpful biomarkers for diagnosis or treatment. This research highlights the potential of targeting the gut microbiome in cancer therapy and provides valuable insights for developing new cancer treatments based on microbiome interactions. Background/Objectives: The role of the gut microbiome in cancer biology has become an increasingly prominent area of research, particularly regarding the role of microbial metabolites and their receptors (MMRs). These metabolites, through the various gut–organ axes, have been proven to influence several pathogenetic mechanisms. This study conducted a comprehensive pan-cancer analysis of MMR transcriptomic profiles across twenty-three cancer types, exploring the mechanisms through which they can influence cancer development and progression. Methods: Utilizing both cancer cell lines from CCLE (Cancer Cell Line Encyclopedia) and human tumor samples from TCGA (The Cancer Gene Atlas), we analyzed 107 MMRs interacting with microbial metabolites such as short-chain fatty acids, bile acids, indole derivatives, and others while studying their interactions with key known cancer genes. Results: Our results revealed that certain MMRs, such as GPR84 and serotonin receptors, are consistently upregulated in various malignancies, while others, like ADRA1A, are frequently downregulated, suggesting diverse roles in cancer pathophysiology. Furthermore, we identified significant correlations between MMR expression and cancer hallmark genes and pathways, including immune evasion, proliferation, and metastasis. Conclusions: These findings suggest that the interactions between microbial metabolites and MMRs may serve as potential biomarkers for cancer diagnosis, prognosis, and therapy, highlighting their therapeutic potential. This study underscores the significance of the microbiota–cancer axis and provides novel insights into microbiome-based strategies for cancer treatment. [ABSTRACT FROM AUTHOR]