Increasing evidence has demonstrated the association between UBASH3A gene and multiple autoimmune diseases (ADs). The aim of our study was to explore the potential effect of UBASH3A messenger RNA (mRNA) expression and its role in the pathogenesis of systemic lupus erythematosus (SLE). UBASH3A mRNA levels were detected by real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) in total RNA, isolated from the peripheral blood mononuclear cells (PBMCs) of 32 SLE patients and 30 healthy donors with TRIzol Reagent. The expression level of UBASH3A mRNA was significantly reduced in PBMCs from SLE patients when compared with healthy controls (p = 0.002). UBASH3A mRNA expression levels in lower active SLE were significantly lower than that in inactive SLE groups (p = 0.000). There was a negative association between mRNA levels of hyper-active and lower-active SLE patients (p = 0.000). Moreover, a significant negative correlation between UBASH3A mRNA expression and the onset age of SLE patients was found (p = 0.044). A negative correlation was found between UBASH3A mRNA expression and SLEDAI (p = 0.049). Nevertheless, no significant difference was found between patients with lupus nephritis (LN) and those without LN (p = 0.392). The presence of leukopenia, positive for anti-dsDNA antibody and anti-SSB antibody were associated with UBASH3A mRNA levels in SLE patients (all p < 0.05). The dysregulation of UBASH3A mRNA levels in SLE patients and their correlations with experimental parameters suggested that UBASH3A may involve in the pathogenesis of SLE.