Patients with autoimmune diseases would be at a higher risk to develop adverse psychological reactions during the coronavirus disease 2019 (COVID-19) pandemic. This study aimed to assess the effect of COVID-19 pandemic on patients with systemic lupus erythematosus (SLE), associated psychological symptoms, disease activity, and quality of life (QoL). Patients and Methods A comparative cross-sectional study was conducted including 97 patients diagnosed as having SLE and consecutively recruited from Zagazig University rheumatology and rehabilitation outpatient clinics, Egypt. An equal number of cross-matched controls were also selected. All participants completed a sociodemographic clinical checklist, symptom checklist 90 scale, fear of COVID-19 scale (FCV-19S), and World Health Organization Quality of Life Scale (WHOQOL-BREF). Additionally, an assessment of disease activity was conducted for the patient group using the SLE disease activity score. Results Patients with SLE, compared with their controls, were more likely to be unemployed, have histories of organic and mental illnesses, and associated with intensified FCV. They had less QoL (physical, social, and total) and higher somatization and Positive Symptom Distress Index scores. Patients with SLE with intensified FCV were more likely to be older (P=0.041), have a history of mental illness (P=0.006), and experience less QoL (physical, environmental, and total) (P=0.046, 0.014, and 0.019, respectively). However, FCV had no association with the disease activity (P=0.280). Conclusions Patients with SLE experienced higher levels of FCV and somatization and lesser QoL during pandemic. There was a robust association between heightened FCV in those patients and reduced QoL. These results highlight the need for early monitoring and management of the potential psychological symptoms developed among those populations during pandemic