Culex quinquefasciatus, a member of the Culex pipiens complex, is widespread in Saudi Arabia and other parts of the world. It is a vector for lymphatic filariasis, Rift Valley fever, and West Nile virus. Studies have shown the deleterious effect of RNA interference (RNAi)-mediated knockdown of various lethal genes in model and agricultural pest insects. RNAi was proposed as a tool for mosquito control with a focus on Aedes aegypti and Anopheles gambiae. In this study, we examined the effect of RNAi of selected target genes on both larval mortality and adult emergence of Cx. quinquefasciatus through two delivery methods: soaking and nanoparticles. Ten candidate genes were selected for RNAi based on their known lethal effect in other insects. Disruption of three genes, chitin synthase-1, inhibitor of apoptosis 1, and vacuolar adenosine triphosphatase, resulted in the highest mortality among the selected genes using the two treatment methods. Silencing the other seven genes resulted in a medium to low mortality in both assays. These three genes are also active against a wide range of insects and could be used for RNAi-based mosquito control in the future.