Pro-inflammatory chemokines and cytokines play an important role in Wallerian degeneration (WD) after peripheral nerve injury. These pro-inflammatory signals are “turned-off” in a timely manner to ensure that the inflammatory response in the injured nerve is limited. The factors that regulate the turning-off of the pro-inflammatory state are not fully understood. The suppressors of cytokine signaling (SOCS) proteins are potential candidates that could limit the inflammatory response by acting to regulate cytokine signaling at the intracellular level. In this work we show that the expression SOCS1 and SOCS3 proteins differ from each other during WD in the mouse sciatic nerve after cut/ligation and crush injuries. SOCS1 is mainly expressed by macrophages and its expression is inversely correlated with phosphorylation of JAK2 and STAT3 signaling proteins and the expression of pro-inflammatory cytokines IL-1β and TNFα. In addition, treatment of cut/ligated nerves, which express lower levels of SOCS1 as compared to crush injury, with a SOCS1 mimetic peptide leads to a decrease in macrophage numbers at 14 days post-injury and reduces IL-1β mRNA expression 1 day post-injury. In contrast, SOCS3 expression is restricted mainly to Schwann cells and is negatively correlated with the expression of IL-6 and LIF. These data suggest that SOCS1 and SOCS3 may play different roles in WD and provide a better understanding of some of the potential regulatory mechanisms that may control inflammation and regeneration in the injured peripheral nerve.