With the increasing rate of chemoresistance in colorectal cancer (CRC) patients with advanced tumor stages, it is a matter of urgent importance to delineate the factors involved in the drug resistance process. In this study, gene expression profiles were downloaded from the Gene Expression Omnibus database and an integrated analysis with the aim of detecting hub long non‑coding RNAs (lncRNAs) and their regulated, differentially expressed genes (DEGs) during treatment with oxaliplatin (OxPt) or irinotecan was conducted. A total of seven differentially expressed lncRNAs were correlated with OxPt resistance and 21 were correlated with resistance to SN‑38, the active metabolite of irinotecan. Gene Ontology annotation and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis confirmed that drug resistance was strongly associated with an imbalance between cell proliferation and apoptosis, cell energetic metabolism under hypoxic conditions, and angiogenesis. Moreover, a large number of lncRNA‑targeted DEGs were located in extracellular exosomes. Further analyses identified four hub lncRNAs involved in the process of drug resistance, including CRNDE, H19, UCA1 and HOTAIR, which are predictive factors for treatment sensitivity. Among them, HOTAIR stands out as a strong factor, the elevated expression of which is also associated with advanced tumor node and metastasis stage and poor CRC disease prognosis.