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Abstract Background Pathogenesis of colorectal cancer (CRC) is connected to deregulation of apoptosis while the effect of lncRNAs, as critical regulatory molecules, on this pathway is not clear well. The present study aimed to identify differential expression of genes and their related lncRNAs which are significantly associated with intrinsic apoptotic pathway in CRC. Methods The connection between CRC and apoptosis was investigated by literature reviews and the genes were enriched by using Enrichr. At the next step, differential expression of enriched genes were evaluated between normal and tumor populations in data sets and were downloaded from GEO. Then, meta-analysis and probe re-annotation were performed. For lncRNAs selection through the highest expression correlation with each of candidate genes, mRNA-lncRNA interaction of screened genes and all of lncRNAs were visualized using Cytoscape. Identified differential expression genes and lncRNAs were validated using TCGA-COAD and the obtained data were confirmed by in vitro studies in the presence of Ag@Glu-TSC nanoparticle as an apoptotic inducer. Cytotoxicity and apoptosis induction effect of Ag@Glu-TSC on Caco-2 cells was determined via MTT and Annexin V/PI, respectively. The expression of genes and lncRNAs were assayed in presence of mentioned nanoparticle. Finally, the expression level of desired genes and lncRNAs were proven in CRC tissues compared to adjacent normal tissues. Results After detection of 48 genes associated with intrinsic apoptosis in CRC according to literature, Enrichr screened 12 common genes involved in this pathway. Among them, 6 genes including BCL2, BCL2L11, BAD, CASP7, CASP9, and CYCS expression reduced in tumor tissue compared to normal according to meta-analysis studies and RNA-seq TCGA data. Afterwards, association of 8 lncRNAs comprising CDKN2B-AS1, LOC102724156, HAGLR, ABCC13, LOC101929340, LINC00675, FAM120AOS, PDCD4-AS1 with more than 5 candidate genes were identified. In vitro studies revealed that four selected lncRNAs including, CDKN2B-AS1, LOC102724156, HAGLR and FAM120AOS were significantly increased in the presence of in optimum concentration of Ag@Glu/TSC and decreased in tumor tissues versus adjacent normal tissues. Conclusion This study developed a new data mining method to screen differentially expressed lncRNAs which are involved in regulation of intrinsic apoptosis pathway in CRC quickly using published gene expression profiling microarrays. Moreover, we could validate a number of these regulators in the cellular and laboratory disease models.