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Colibactin is a genotoxin produced primarily by <i>Escherichia coli</i> harboring the genomic <i>pks</i> island (<i>pks</i>⁺ <i>E. coli</i>). <i>Pks</i>⁺ <i>E. coli</i> cause host cell DNA damage, leading to chromosomal instability and gene mutations. The signature of colibactin-induced mutations has been described and found in human colorectal cancer (CRC) genomes. An inflamed intestinal environment drives the expansion of <i>pks</i>⁺ <i>E. coli</i> and promotes tumorigenesis. Mesalamine (i.e., 5-aminosalycilic acid), an effective anti-inflammatory drug, is an inhibitor of the bacterial polyphosphate kinase (PPK). This drug not only inhibits the production of intestinal inflammatory mediators and the proliferation of CRC cells, but also limits the abundance of <i>E. coli</i> in the gut microbiota and diminishes the production of colibactin. Here, we describe the link between intestinal inflammation and colorectal cancer induced by <i>pks</i>⁺ <i>E. coli</i>. We discuss the potential mechanisms of the pleiotropic role of mesalamine in treating both inflammatory bowel diseases and reducing the risk of CRC due to <i>pks</i>⁺ <i>E. coli</i>.