Infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of coronavirus disease 2019 (COVID-19), may elicit uncontrolled and damaging inflammatory reactions, due to an excessive immune response and dysregulated production of cytokines and chemokines. Thus, it is critical to identify compounds able to inhibit virus replication and thwart the excessive inflammatory reaction and tissue lesions secondary to SARS-CoV-2 infection. Here, we show that the neuropeptides VIP and PACAP, molecules endowed with immunoregulatory properties, were able to inhibit SARS-CoV-2 RNA synthesis/replication in human monocytes and viral production in lung epithelial cells. VIP and PACAP protected these cells from virus-induced cytopathicity, reduced the production of proinflammmatory mediators, and prevented the SARS-CoV-2-induced NF-kB activation, which is critically involved in the production of inflammatory mediators. Both neuropeptides promoted CREB activation in infected monocytes, a transcription factor with antiapoptotic activity and also a negative regulator of NF-kB. As a possible host response to control patient inflammation, we identified that VIP levels were elevated in plasma from patients with severe forms of COVID-19, correlating with the inflammatory marker CRP and survival on those patients. Since a synthetic form of VIP is clinically approved in Europe and under two clinical trials for patients with COVID-19, our results provide the scientific evidence to further support clinical investigation of these neuropeptides against COVID-19.