Background Evaluation of disease activity in systemic lupus erythematosus (SLE) patients is important for modulating the therapeutic plan and decreasing organ damage. Autoantibodies are important serological biomarkers in SLE. We evaluated the effect of co-positivity of anti-dsDNA, anti-nucleosome, and anti-smith, autoantibodies on the SLEDAI score in SLE patients. Results Eighty adult SLE patients were included in this study. The correlations of the three autoantibodies with the SLEDAI score in addition to their sensitivity and specificity for the assessment of disease activity were analyzed. There was a highly significant difference between anti-dsDNA, anti-nucleosome, and anti-smith positive and negative groups as regards the SLEDAI score. Increased number of autoantibody positivity was associated with an increased mean rank of SLEDAI, and the three autoantibodies were positively correlated with each other and with the SLEDAI score. Roc curve analysis revealed that anti-smith has the highest sensitivity (90%) followed by anti-dsDNA and anti-nucleosome (85% for each). Moreover, anti-dsDNA had the highest specificity (88%) followed by anti-nucleosome (86%) then anti-smith (84%). Conclusions Anti-dsDNA, anti-nucleosome, and anti-smith autoantibodies have a positive correlation with the SLEDAI score, and they may be considered as good serological biomarkers for the assessment of disease activity in SLE patients.