<p>This study aimed to identify differentially expressed long non-coding RNAs (lncRNAs) and messenger RNAs (mRNAs) in damaged cartilage (DC) and un-damaged cartilage (UDC) in human osteoarthritis (OA), exploring their roles in disease progression through bioinformatics analysis and ceRNA network construction. Cartilage samples from 5 OA patients undergoing total knee arthroplasty were analyzed. RNA sequencing was used to detect the expression of lncRNAs and mRNAs in DC and UDC samples. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to investigate biological processes. A ceRNA network was constructed, and differentially expressed RNAs were validated by quantitative real-time polymerase chain reaction (qRT-PCR). In the damaged cartilage (DC) samples, 5 lncRNAs were significantly upregulated, and 15 were significantly downregulated, while 8 mRNAs were upregulated, and 8 were downregulated. The differential expression of lncRNAs, including LINC01411, AL596087.2, PCDH20, LRFN2, and AL583785.1, was confirmed using qRT-PCR, with <i>p</i>-values for all results showing statistical significance (<i>p</i> &lt; 0.05). GO/KEGG enrichment analysis revealed key pathways such as Ras, PI3K-Akt, and MAPK that were significantly involved in OA pathogenesis. The ceRNA network construction highlighted crucial miRNA interactions, identifying potential regulators of cartilage-related biological processes. Differentially expressed lncRNAs and mRNAs are involved in critical signaling pathways in OA cartilage, suggesting their potential as biomarkers or therapeutic targets for OA treatment. Further functional studies are needed to fully elucidate their roles in OA pathogenesis.</p>