BACKGROUND To investigate the value of D-dimer combined with red blood cell distribution width (RDW) in evaluating the disease activity of systemic lupus erythematosus (SLE). METHODS A total of 105 SLE patients confirmed in our hospital from July 2018 to September 2020 were collected as the SLE group, and 60 healthy persons matched in age and gender during the same period were collected as the control group. According to the SLEDAI score, SLE patients were divided into SLE active group and SLE inactive group, and RDW and D-Dimer levels were detected. RESULTS The level of RDW in the SLE active group [14.8 (13.4, 16.8)] was significantly higher than that in the SLE inactive group [13.4 (12.6, 14.37)] and control group [12.3 (12, 12.7)], with statistically significant differences (p < 0.05). The D-dimer level in the SLE active group was 1.36 (0.9, 2.25) mg/L, which was significantly higher than that in SLE inactive group [0.34 (0.22, 0.52)] mg/L and control group [0.15 (0.08, 0.19)] mg/L, with statistically significant differences (p < 0.05). Both RDW and D-dimer were positively correlated with the SLEDAI score (r = 0.393, p = 0.000), (r = 0.483, p = 0.000). The results of receiver operating characteristic curve showed that the area under the curve of RDW and D-Dimer alone was 0.875 and 0.954, respectively, while the area under the curve of RDW combined with D-Dimer was the largest, 0.984. CONCLUSIONS The levels of RDW and D-dimer are closely related to the disease activity of SLE patients, and RDW combined with D-dimer is more valuable in assessing the disease activity of SLE patients.