Although an imbalanced gut microbiome is closely associated with colorectal cancer (CRC), how the gut microbiome affects CRC is not known. Long non-coding RNAs (lncRNAs) can affect important cellular functions such as cell division, proliferation, and apoptosis. The abnormal expression of lncRNAs can promote CRC cell growth, proliferation, and metastasis, mediating the effects of the gut microbiome on CRC. Generally, the gut microbiome regulates the lncRNAs expression, which subsequently impacts the host transcriptome to change the expression of downstream target molecules, ultimately resulting in the development and progression of CRC. We focused on the important role of the microbiome in CRC and their effects on CRC-related lncRNAs. We also reviewed the impact of the two main pathogenic bacteria, Fusobacterium nucleatum and enterotoxigenic Bacteroides fragilis, and metabolites of the gut microbiome, butyrate, and lipopolysaccharide, on lncRNAs. Finally, available therapies that target the gut microbiome and lncRNAs to prevent and treat CRC were proposed.