Tissue damage from ischemia reperfusion IR injury occurs when blood supply is restored to the tissue following a period of ischemia, such as after a traumatic injury and subsequent repair. A significant source of tissue damage following IR injury is also due to the intense immune system reaction. Here, we target the early immune involvement, specifically neutrophils, to target neutrophil extracellular trap formation to mitigate tissue damage following IR injury. In a mouse model of IR injury, we have investigated multiple PAD4 pathway inhibitors Cl-Amidine and GDK-199 and found that while these treatments do decrease NET formation in the tissue, a significant reduction in muscle fibrosis was not achieved. However, targeting a different NET-related pathway, TLR9 inhibition, with hydroxychloroquine Plaquenilregistered trademark was shown to decrease IR related skeletal muscle fibrosis and increase muscle regeneration at 5 and 7 days post injury.