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Simple Summary: Lung adenocarcinoma, the most prevalent type of lung cancer, presents a significant treatment challenge owing to drug resistance. This study aimed to investigate the role of long non-coding RNAs (lncRNAs) in promoting intrinsic resistance in three lung adenocarcinoma cell lines from the onset of treatment. Drug-tolerant persister (DTP) cells, a subset of cancer cells with the ability to survive and proliferate after exposure to therapeutic drugs, were generated. RNA sequencing was used to investigate the differential expression of lncRNAs, and the clinical relevance of lncRNAs was assessed in a cohort of lung adenocarcinoma patients from The Cancer Genome Atlas. Knockdown of these lncRNAs increases the sensitivity of the analyzed cell lines to therapeutic drugs. This study provides an opportunity to investigate the role of lncRNAs in the genetic and epigenetic mechanisms underlying intrinsic resistance. Lung adenocarcinoma is the most prevalent form of lung cancer, and drug resistance poses a significant obstacle in its treatment. This study aimed to investigate the overexpression of long non-coding RNAs (lncRNAs) as a mechanism that promotes intrinsic resistance in tumor cells from the onset of treatment. Drug-tolerant persister (DTP) cells are a subset of cancer cells that survive and proliferate after exposure to therapeutic drugs, making them an essential object of study in cancer treatment. The molecular mechanisms underlying DTP cell survival are not fully understood; however, long non-coding RNAs (lncRNAs) have been proposed to play a crucial role. DTP cells from lung adenocarcinoma cell lines were obtained after single exposure to tyrosine kinase inhibitors (TKIs; erlotinib or osimertinib). After establishing DTP cells, RNA sequencing was performed to investigate the differential expression of the lncRNAs. Some lncRNAs and one mRNA were overexpressed in DTP cells. The clinical relevance of lncRNAs was evaluated in a cohort of patients with lung adenocarcinoma from The Cancer Genome Atlas (TCGA). RT–qPCR validated the overexpression of lncRNAs and mRNA in the residual DTP cells and LUAD biopsies. Knockdown of these lncRNAs increases the sensitivity of DTP cells to therapeutic drugs. This study provides an opportunity to investigate the involvement of lncRNAs in the genetic and epigenetic mechanisms that underlie intrinsic resistance. The identified lncRNAs and CD74 mRNA may serve as potential prognostic markers or therapeutic targets to improve the overall survival (OS) of patients with lung cancer. [ABSTRACT FROM AUTHOR]