This study aimed to investigate immune-related pathophysiology of the temporomandibular joint (TMJ) osteoarthritis (OA) in young females by analyzing transcriptional profiles of peripheral blood mononuclear cells. The RNA-sequencing (RNA-seq) was conducted on 24 young females with TMJ OA (mean age 19.3 ± 3.1 years) (RNAOA) and 11 age and sex matched healthy controls (mean age 20.5 ± 3.7 years) (CON). RNA-seq datasets were analyzed to identify genes, pathways, and regulatory networks of those which were involved in the development of TMJ OA. RNA-seq data analysis revealed 41 differentially expressed genes (DEGs) between RNAOA and CON. A total of 16 gene ontology (GO) terms including three molecular and 13 biological terms were annotated via the GO function of molecular function and biological process. Through ingenuity pathway analysis (IPA), 21 annotated categories of diseases and functions were identified. There were six hub genes which showed significant results in both GO enrichment analysis and IPA, namely HLA-C, HLA-F, CXCL8, IL11RA, IL13RA1, and FCGR3B. The young females with TMJ OA showed alterations of the genes related to immune function in the blood and some of changes may reflect inflammation, autoimmunity, and abnormal T cell functions.