Arenaviruses such as Lassa virus cause arenavirus hemorrhagic fever (AVHF), but protective vaccines and effective antiviral therapy remain unmet medical needs. Our prior work has revealed that inducible nitric oxide synthase (iNOS) induction by IFN-γ represents a key pathway to microvascular leak and terminal shock in AVHF. Here we hypothesized that Ruxolitinib, an FDA-approved JAK inhibitor known to prevent IFN-γ signaling, could be repurposed for host-directed therapy in AVHF. We tested the efficacy of Ruxolitinib in MHC-humanized (HHD) mice, which develop Lassa fever-like disease upon infection with the monkey-pathogenic lymphocytic choriomeningitis virus strain WE. Anti-TNF antibody therapy was tested as an alternative strategy owing to its expected effect on macrophage activation. Ruxolitinib but not anti-TNF antibody prevented hypothermia and terminal disease as well as pleural effusions and skin edema, which served as readouts of microvascular leak. As expected, neither treatment influenced viral loads. Intriguingly, however, and despite its potent disease-modifying activity, Ruxolitinib did not measurably interfere with iNOS expression or systemic NO metabolite levels. These findings suggest that the FDA-approved JAK-inhibitor Ruxolitinib has potential in the treatment of AVHF. Moreover, our observations indicate that besides IFN-γ-induced iNOS additional druggable pathways contribute essentially to AVHF and are amenable to host-directed therapy.