To explore the significance of LINC02082 and LOC105369812 in the differential diagnosis of papillary thyroid carcinoma (PTC) and benign nodules. Cancer tissues and benign nodules from 8 patients were sequenced and constructed using high-throughput sequencing. Differentially expressed mRNAs (DEmRNAs) and lncRNAs (DElncRNAs) with significant differences were screened. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed on the mRNAs co-expressed by DEmRNAs and DElncRNAs. LncRNAs with significant differences, good consistency, and enrichment in the PI3K-AKt signaling pathway were selected as candidate lncRNAs, and the target lncRNAs were screened by correlation analysis. Target lncRNAs and co-expressed mRNAs enriched in the PI3K-AKt signaling pathway and microRNAs (miRNAs) interacting with each other were used to construct a competing endogenous RNA (ceRNA) network. Finally, the PTC-related gene set (GSE33630) was downloaded from the GEO database and the expression of the genes obtained by sequencing was compared. Differential expression was verified using quantitative real-time PCR (qRT-PCR). Finally, the receiver operating characteristic (ROC) curve was used to evaluate the value of the target lncRNAs in diagnosis, when used alone or in combination. A total of 1113 differential RNAs (DE RNAs) were identified, of which 338 were DElncRNAs and 775 were DEmRNAs. Three lncRNAs enriched in the PI3K-AKt signaling pathway, LINC02082, LOC105369812, and LOC105375170, were used as candidate lncRNAs. After correlation analysis with known biomarkers, LINC02082 and LOC105369812 were selected as the target lncRNAs. The qRT-PCR results showed that the target lncRNAs were significantly different among the 3 tissues. The ROC curve showed that LOC105369812 could be used to differentiate PTC from benign thyroid nodules, whereas LINC02082 and its combination had lower predictive value. LOC105369812 is valuable for differentiating benign from malignant thyroid nodules, whereas LINC02082 has lower diagnostic value.