Abstract Objectives This study aimed to evaluate the activity of the glymphatic system in SLE using a diffusion-based method termed ‘Diffusion Tensor Image Analysis aLong the Perivascular Space (DTI-ALPS)’, and to examine its correlations with morphological changes in the brain. Methods In this cross-sectional study, 45 female patients with SLE and 30 healthy controls (HCs) were included. Voxel-based and surface-based morphometric analyses were performed to examine T1-weighted images, and diffusion tensor images were acquired to determine diffusivity along the x-, y- and z-axes in the plane of the lateral ventricle body. The DTI-ALPS index (ALPS index) was calculated for each patient. The differences in values between patients with SLE and the HC group were compared using the independent samples t test or the Mann–Whitney U test. To determine correlations between the ALPS index and brain morphological parameters, partial correlation analysis and Pearson’s correlation analysis were conducted. Results Patients with SLE showed lower values for the ALPS index in the left (1.543 ± 0.141 vs 1.713 ± 0.175, P < 0.001), right (1.428 ± 0.142 vs 1.556 ± 0.139, P < 0.001) and whole (1.486 ± 0.121 vs 1.635 ± 0.139, P < 0.001) brain compared with the HC group. Reduced ALPS index showed significant positive correlations with grey matter loss. Conclusion The non-invasive ALPS index could serve as a sensitive and effective neuroimaging biomarker for individually quantifying glymphatic activity in patients with SLE. Glymphatic system abnormality may be involved in the pathophysiologic mechanism underlying CNS damage in SLE patients.