Emicizumab is a bispecific chimeric humanized IgG4 that mimics the procoagulant activity of factor VIII (FVIII). Its long half-life and subcutaneous injection route have been life-changing in treating patients with hemophilia A (PwHA) with and without FVIII inhibitors. However, emicizumab only partially mimics FVIII activity; it prevents but does not treat acute bleeds. Emergency management is particularly complicated in patients with FVIII inhibitors on emicizumab prophylaxis, wherein exogenous FVIII is inefficient. We have shown recently that Imlifidase, an IgG-degrading enzyme (IdeS) of bacterial origin, efficiently eliminates human anti-FVIII IgG in a mouse model of severe HA with inhibitors and opens a therapeutic window for the administration of therapeutic FVIII. Here, we investigated the impact of IdeS treatment in HA mice injected with emicizumab. IdeS hydrolyzed emicizumab in vitro and in vivo, albeit at slower rates than another recombinant human monoclonal IgG4. While the F(ab’)2 fragments were rapidly cleared from the circulation, thus leading to a rapid loss of emicizumab procoagulant activity, low amounts of the single-cleaved intermediate IgG persisted for several days. Moreover, the IdeS-mediated elimination of the neutralizing anti-FVIII IgG and restoration of the hemostatic efficacy of exogenous FVIII were not impaired by the presence of emicizumab and polyclonal human IgG in inhibitor-positive HA mice. Our results suggest that IdeS could be administered to inhibitor-positive PwHA under emicizumab prophylaxis to improve and ease the management of breakthrough bleeds or programmed major surgeries.