RNA interference is one of the fastest developing fields in biological science and has been demonstrated as a promising therapy for a wide range of viral infections. This highly specific suppression can be achieved by the introduction of short interfering (si) RNAs into mammalian systems, resulting in the efficient reduction of viral load in vitro. However, this activity can have the unfortunate consequence of non-specifically activating several innate immune sensors including toll-like receptor (TLR) 7/8 and stimulate the expression of interferon, which can mask the true specific effects of the siRNA. While often not desired, the localised activation of TLR pathways in combination with specific anti-viral activity of the siRNA may have a beneficial role in providing a more potent control of viral infection, especially in reducing transmission between hosts. Here we show that specific TLR agonists are able to induce cytokines of the innate immune response and improve the anti-viral response when used in tandem with siRNAs targeting specific viral sequences in a Semliki Forest Virus model. Furthermore, individual pre-treatment of HeLa cells with poly(I:C) or viral nucleocapsid siRNA before Hendra virus (HeV) infection resulted in a 1.5 log (>95%) reduction while the combination resulted in a 2.5 log (>99.9%) reduction in titre, indicating a trend for the two pre-treatments to act simultaneously to cause additional suppression of HeV. This foundation will allow further investigation into in vivo systems and once matched with efficient delivery mechanisms may result in better viral control and a new treatment modality for acute viral infections.