Systemic lupus erythematous (SLE) is an autoimmune and inflammatory disease that can affect all organs of the body. The purpose of this quantitative cross-sectional study was to examine SLE-related issues associated with depression and work-productivity impairment, and to assess if depression mediated the relationship between SLE disease activity and damage and work-productivity impairment. Participants were 257 residents of the state of Georgia in the United States with SLE and were recruited from the Georgians Organized Against Lupus study. Bandura'€™s social cognitive theory was the guiding theoretical framework of the study. Findings showed that the majority of participants worked full time (78.2%), identified as Black (72.8%), female (94.2%), above poverty level (77.4%), and had private health insurance (70.0%). Mean and median score results indicated that participants missed, on average, slightly less than half a day of work every 7 days, and had mild-to-moderate levels of work productivity impairment. Mean and median scores showed that participants reported mild-to-moderate levels of SLE disease activity and damage and depression. Linear regression results revealed significant relationships between SLE activity and damage and work productivity impairment. Hierarchical linear regression for mediation findings indicated that depression partially mediated the relationship between SLE disease activity and damage and work productivity impairment. The findings from this study might help to increase stakeholder awareness of SLE disease activity and damage and SLE effects on depression and work functioning.