Chronic hepatitis C virus (HCV) infection is one of the leading causes of liver cancer and liver transplantation worldwide. No vaccine is available for preventing the spread of HCV, and the current therapeutic regimen is only moderately effective and causes serious side effects. New antiviral agents are required to treat HCV infection, but the high mutation rate of HCV hinders the effectiveness of virus-specific inhibitors. Targeting the host enzymes required for HCV to replicate offers a promising new direction for antiviral therapy. During infection, HCV promotes excessive fat accumulation in the liver, which benefits the virus as this promotes formation of lipid droplets, a cellular organelle essential for assembly of new HCV infectious viral particles. Here, we report the development of a specific inhibitor targeting SKI-1/S1P, a host enzyme required for lipid production in human cells. We show that inhibiting SKI-1/S1P activity in human liver cells effectively blocks lipid droplet formation and HCV infection. Many prevalent human viruses, such as dengue, rotavirus, and hepatitis B virus, hijack host lipid metabolic pathways similar to those targeted by HCV to complete their lifecycle. Thus, we propose that cellular SKI-1/S1P is a potential target for developing desperately needed novel broad-spectrum antiviral drugs.