This study was conducted to explore hippocampal structural changes and their possible associations with clinical characteristics, emotional status, and treatment regimens in patients with systemic lupus erythematosus (SLE) without major neuropsychiatric manifestations (non-NPSLE). Eighty-five non-NPSLE patients with normal conventional magnetic resonance imaging (MRI) and seventy-seven matched healthy control (HC) subjects were recruited. All participants underwent the standard high-resolution volumetric MRI. The bilateral hippocampal volume (HIPV) and hippocampal density (HIPD) were calculated, respectively, for each participant. We found that the bilateral HIPV and HIPD of the SLE patient group were significantly less than those of the HC group. The bilateral HIPV of female patients were significantly less than those of male patients. The SLE disease activity index (SLEDAI) was negatively correlated with the bilateral HIPV and the right HIPD. Urine protein quantity was negatively correlated with the bilateral HIPV and HIPD. Hydroxychloroquine (HCQ) showed a protective effect on right HIPV. In conclusion, we found that the early hippocampal atrophy could occur before obvious neuropsychiatric manifestations and might be associated with SLE disease activity and organ damages. Early detection and intervention of hippocampal damage might prevent the progression to NPSLE. More studies are needed to fully understand the underlying mechanisms of hippocampal atrophy in SLE. © 2020 Shuang Liu et al.