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 introducing siRNAs into mammalian systems and results 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 TLR7/8 and stimulating 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 the 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 TLR3, TLR7 and TLR9 agonists are able to induce cytokines involved in the innate immune response and can improve the anti-viral response when used in tandem with siRNAs targeting specific viral sequences. 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.