Abstract Hemophagocytic lymphohistiocytoses (HLH) is a heterogeneous group of disorders characterized by severely damaging immune responses. In HLH, activated CD8+ T cells and macrophages overproduce pro-inflammatory cytokines, which contribute greatly to morbidity and mortality. In a murine preclinical model, HLH is recapitulated by infecting perforin knockout mice with lymphocytic choriomeningitis virus (LCMV). The inability of CD8+ T cells to kill infected cells results in a high production of inflammatory cytokines and ultimately death. We recently reported that treatment with the JAK1/2 inhibitor ruxolitinib significantly reduces the manifestations of HLH in this model. In this study, we sought to: 1) compare the effect of ruxolitinib treatment with IFN-γ blockade (currently in clinical trials) in the acute phase and 2) determine the long-term effects of treatment upon discontinuation. On day 9 p.i., ruxolitinib treatment was superior to IFN-γ blockade in reducing splenomegaly, numbers of inflammatory foci in the liver, LCMV-specific hepatic CD8+ T cells, and splenic IFN-γ+TNF-α+ CD8+ T cells. Surprisingly, on day 35 p.i., ruxolitinib treated mice achieved 100% survival, while only 20% of the IFN-γ Ab-treated mice survived. Since ruxolitinib dampens inflammation, we hypothesized that lower inflammation and viral persistence would induce T cell exhaustion. Indeed, CD8+ T cells stimulated with LCMV-specific peptide produced less IFN-γ and TNF-α. In addition, a significant population of CD8+CD44hi T cells co-expressed PD-1 and Tim-3. This was also correlated with enhanced percentages of Foxp3+CD4+ Tregs in treated mice. Overall, this study provides evidence and mechanistic insight for ruxolitinib as a novel treatment for HLH.