A dynamic actin cytoskeleton is necessary for viral entry, intracellular migration, and virion release. For HIV-1 infection, during entry, the virus triggers early actin activity through hijacking chemokine coreceptor signaling which activates a host dependency factor cofilin and its kinase, the LIM domain kinase (LIMK). Although knockdown of human LIMK1 with shRNA inhibits HIV infection, no specific small molecule inhibitor of LIMK was available. Here we describe the design and discovery of novel classes of small molecule inhibitors of LIMK for inhibiting HIV infection. We identified R10015 as a lead compound that blocks LIMK kinase activity by binding to the ATP-binding pocket. R10015 specifically blocks viral DNA synthesis, nuclear migration, and virion release. In addition, R10015 inhibits multiple viruses including EBOV, RVFV, VEEV, and HSV-1, suggesting that LIMK inhibitors could be developed as a new class of broad-spectrum anti-viral drugs.