The objective of this study was to elucidate the proteomic and transcriptomic alterations within the cartilage in Kashin-Beck disease (KBD) compared to a normal control. We conducted a comparison of the expression profiles of proteins, mRNAs, and lncRNAs via data-independent acquisition (DIA) proteomics and transcriptome sequencing in six KBD individuals and six normal individuals. To facilitate the functional annotation enrichment analysis of the differentially expressed (DE) proteins, DE mRNAs, and DE lncRNAs, we employed bioinformatic analysis utilizing Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG). Additionally, we conducted integration analysis of multi-omics datasets using mixOmics. We revealed a distinct proteomic signature, highlighting 53 DE proteins, with notable alterations in the pathways related to tryptophan metabolism and microbial metabolism. Additionally, we identified 160 DE mRNAs, with the functional enrichment analysis uncovering pathways related to RNA metabolism and protein splicing. Furthermore, our analysis of the lncRNAs demonstrated biological processes involved in protein metabolism and cellular nitrogen compound metabolic processes. The integrative analysis uncovered significant correlations, including the positive correlation between superoxide dismutase 1 () and mitochondrial import receptor subunit TOM6 homolog (TOMM6), and the negative correlation between C-X9-C motif-containing 1 () and succinate-CoA ligase [GDP-forming] subunit beta, mitochondrial (SUCLG2). Our results provide novel insights into the molecular mechanisms underlying KBD.