Osteoarthritis (OA) is one of the most common refractory degenerative joint diseases worldwide. Synovitis is believed to drive joint cartilage destruction during OA pathogenesis. Cuproptosis is a novel form of copper-induced cell death. However, few studies have examined the correlations between cuproptosis-related genes (CRGs), immune infiltration, and synovitis. Therefore, we analyzed CRGs in synovitis during OA. Microarray datasets (GSE55235, GSE55457, GSE12021, GSE82107 and GSE176308) were downloaded from the Gene Expression Omnibus database. Next, we conducted differential and subtype analyses of CRGs across synovitis. Immune infiltration and correlation analyses were performed to explore the association between CRGs and immune cell abundance in synovitis. Finally, single-cell RNA-seq profiling was performed using the GSE176308 dataset to investigate the expression of CRGs in the various cell clusters. We found that the expression of five CRGs (FDX1, LIPT1, PDHA1, PDHB, and CDKN2A) was significantly increased in the OA synovium. Moreover, abundant and various types of immune cells infiltrated the synovium during OA, which was correlated with the expression of CRGs. Additionally, single-cell RNA-seq profiling revealed that the cellular composition of the synovium was complex and that their proportions varied greatly as OA progressed. The expression of CRGs differed across various cell types in the OA synovium. The current study predicted that cuproptosis may be involved in the pathogenesis of synovitis. The five screened CRGs (FDX1, LIPT1, PDHA1, PDHB, and CDKN2A) could be explored as candidate biomarkers or therapeutic targets for OA synovitis.