Objectives To measure the expression level of the vacuolar protein sorting 13 (VPS13) gene and stimulator of interferon genes (STING) in patients with SLE with and without reported neuropsychiatric symptoms to establish their possible role in the pathogenesis of neuropsychiatric SLE (NPSLE). Methods This study included 100 subjects: 50 patients diagnosed with SLE and 50 age-matched and sex-matched healthy participants as the control group. The patients with SLE were further subdivided into NPSLE and non-NPSLE groups. All the subjects underwent rheumatological, neurological and psychological evaluation, MRI, VPS13C gene and STING expression assessment via quantitative real-time PCR. Results Seventy-eight per cent of the SLE group were classified as non-NPSLE, and 22% were classified as NPSLE. Positive MRI results were found in 55% of the patients with NPSLE and 7.7% of the patients without NPSLE. VPS13C expression levels were decreased in the patients with SLE compared with the control (p<0.001), while STING expression levels showed higher levels in the patients in comparison with the control (p<0.001). Both markers showed significant differences between the MRI-positive and MRI-negative groups. At a cut-off value of 0.225 for the VPS13C assessment and a cut-off value of 3.15 for STING expression, both markers were able to distinguish patients with NPSLE from those who were non-NPSLE; however, VPS13C performed better. Conclusion The VPS13C expression levels were decreased in patients with NPSLE compared with patients without NPSLE, while STING expression levels showed higher levels in NPSLE. Both were associated with the MRI findings. To distinguish patients with NPSLE from those without it, the VPS13C assessment performed better.