Small interfering RNA (siRNA) delivery can provide an effective therapy for treating viral diseases by silencing genes involved in viral replication. In this study, a liver‐targeting formulation of lipidoid nanoparticle for delivery of siRNA that targets protein kinase C‐related kinase 2 (PRK2) to inhibit hepatitis C virus (HCV) replication is reported. The most effective, minimally cytotoxic lipidoid for siRNA delivery to hepatic cells is identified from a small library of alkyl epoxide–polyamine conjugates. In vitro transfection of PRK2 siRNA (siPRK2) using this lipidoid induces significant silencing of PRK2 (≈80%), suppressing HCV replication in human hepatic cells transfected with the HCV subgenomic replicon. Systemic administration of siPRK2 using the lipidoid nanoparticles results in significant reduction of host PRK2 in the mouse liver (≈60%). This treatment significantly suppresses HCV replication in an HCV‐xenograft mouse model. siRNA delivery to the liver is further improved via galactosylation of the lipidoid. Compared with the unmodified lipidoid formulation, galactosylated lipidoids induce greater silencing of host PRK2 in mouse livers (≈80%) and more rapid suppression of HCV replication in an HCV‐xenograft mouse. This study suggests that galactosylated lipidoid nanoparticles could provide a treatment for hepatitis C by mediating delivery of anti‐viral RNA interference therapeutics to the liver.