Targeting host pathways that are exploited by viruses represents a promising antiviral strategy. Bekerman et al. show that the host cell kinases AP2-associated protein kinase 1 (AAK1) and cyclin G-associated kinase (GAK), which activate the host adapter proteins AP1 and AP2, are required by hepatitis C virus, dengue virus (DENV) and Ebola virus (EBOV) for host infection. In cells, the anticancer kinase inhibitors sunitinib and erlotinib (which inhibit AAK1 or GAK) exhibited antiviral activity against multiple viruses. In mouse models of DENV and EBOV infections, the combination of both drugs reduced viral load and increased survival.