Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by the involvement of multiple organs and dysregulation of the immune system. Zinc finger (ZNF) proteins act as DNA-binding transcription factors, thereby regulating gene expression. Polymorphisms, specifically single-nucleotide polymorphisms (SNPs), within ZNF-coding genes, have been implicated in susceptibility to autoimmune diseases, including the ZNF-76 gene in SLE. This investigation aimed to elucidate the association between ZNF-76 gene expression, protein levels, and rs10947540 SNP in a cohort of Egyptian SLE patients. One hundred healthy controls and one hundred SLE patients were recruited. Quantitative real-time PCR was employed to identify ZNF-76 (C/T) rs10947540 genotypes and quantify serum ZNF-76 mRNA expression. Additionally, serum ZNF-76 protein levels were measured using ELISA. Our results revealed downregulation of ZNF-76 mRNA expression in approximately 75% of SLE patients, with a significant decrease (0.23-fold) in median expression compared to controls. Furthermore, SLE patients exhibited a higher prevalence of high-risk TT genotype and demonstrably lower serum ZNF-76 protein levels. In conclusion, this study suggests a strong association between decreased serum ZNF-76 mRNA expression and increased susceptibility to SLE in the studied Egyptian population. Specific SNP in the ZNF-76 gene may be potential markers for inherited predisposition to SLE in this population.