Long non-coding RNAs (lncRNAs) were reported to have the potential in maintaining genome instability, but the identification of lncRNAs related to genome instability and their prognostic value have not been largely explored in colon cancer. In this study, we obtained 155 genome instability-associated lncRNAs based on somatic mutation profiles in colon cancer from The Cancer Genome Atlas (TCGA) database. Functional enrichment analysis revealed the possible roles of genes co-expressed with those lncRNAs involved in some cancer, genome instability and immune related biological processes. Combined with overall survival data, a seven-lncRNA signature was established for prognosis prediction. According to the risk score calculated by this signature, high-risk patients characterized by high somatic mutation count, high microsatellite instability, significantly poorer clinical outcomes and specific tumor immune infiltration status compared with low-risk patients. The lncRNA signature was validated to be an independent prognostic indicator with good predictive performance in TCGA cohort. Furthermore, the prognostic value of the ZNF503-AS1 in lncRNA signature was confirmed in another independent dataset from Gene Expression Omnibus database. In summary, the genome instability-associated lncRNA signature in this study could be a promising tool for effectively predicting survival outcomes in colon cancer.