Gain-of-function polymorphisms in the transcription factor IFN regulatory factor 5 (IRF5) are associated with an increased risk of developing systemic lupus erythematosus. Global homozygous or heterozygous deficiency of IRF5 from birth confers protection in many lupus mouse models. However, less is known about the effects of IRF5 targeting after autoimmunity has already developed. This is an important point to clarify when considering IRF5 as a potential therapeutic target in lupus. In this study, we demonstrate that genetic reduction of IRF5 expression after disease initiation reduces disease severity in the FcγRIIB−/− Y-linked autoimmune accelerating mouse lupus model. Reduction of IRF5 expression resulted in a decrease in splenomegaly and lymphadenopathy and a reduction in splenic B cell activation and plasmablast numbers. Splenic T cell activation and differentiation were also impacted as demonstrated by an increase in the number of naive CD4+ and CD8+ T cells and a reduction in the number of memory/effector CD4+ and CD8+ T cells. Although serum antinuclear autoantibody levels were not altered, reduction in IRF5 expression led to decreased immune complex deposition and complement activation, diminished glomerular and interstitial disease, and a reduction in immune cell infiltrate in the kidney. Mechanistically, myeloid cells in the kidney produced less inflammatory cytokines after TLR7 and TLR9 activation. Overall, we demonstrate that genetic reduction of IRF5 expression during an active autoimmune process is sufficient to reduce disease severity. Our data support consideration of IRF5 as a therapeutic target and suggest that approaches targeting IRF5 in systemic lupus erythematosus may need to impact IRF5 activity both systemically and in target organs.