Severe dengue is characterized by thrombocytopenia, hemoconcentration, cytokine storm, and vascular leakage. Beyond the exacerbated pro-inflammatory responses observed during the acute phase, we have identified that severe dengue is also associated with a failure in the resolution of inflammation mediated by annexin A1 (AnxA1). Patients with severe dengue exhibit lower plasma levels of AnxA1 compared with individuals with mild dengue or non-infected controls. Consistently, annexin A1 knockout (AnxA1 KO) mice and mice lacking its receptor, FPR2, develop a more severe disease phenotype characterized by thrombocytopenia, hemoconcentration, vascular leakage, and increased levels of CCL2 and IFN-γ. Notably, no differences in viral titers were observed. In addition, disease resolution is delayed in these mice, suggesting that the AnxA1–FPR2 pathway plays a critical role in the resolution of dengue-induced inflammation. Importantly, administration of Ac2-26, an AnxA1 mimetic peptide, significantly ameliorates severe dengue manifestations. These effects are further enhanced when Ac2-26 is formulated in cyclodextrins and administered orally. In vitro, Ac2-26 reduced the activation of DENV-infected dendritic cells and decreased TNF production. The peptide also reduced cytokine production and vascular permeability in HUVECs, as well as mast cell degranulation and MCPT-1 release. Furthermore, Ac2-26 prevented thrombocytopenia through a mechanism dependent on P2Y12–P-selectin–mediated platelet activation and platelet–leukocyte aggregation, both in vitro and in vivo. Finally, combined treatment with an antiviral drug resulted in 100% protection from lethality in A129 mice. Similar protective effects were observed in models of CHIKV infection, in which the peptide ameliorated hypernociception and inflammation, and in coronavirus infections, improving lung damage, inflammation, and pulmonary function. Interestingly, other pro-resolving mediators, such as angiotensin-(1–7) and melanocortin agonists, exert similar protective effects, highlighting failure of inflammation resolution as a critical pathogenic mechanism and therapeutic target in acute viral infections. Together, these findings suggest that pro-resolving mediators such as AnxA1 represent a promising host-directed therapeutic strategy and could be used as adjunct therapy for dengue and other viral infectious diseases.