The morbillivirus genus includes important pathogens such as measles virus (MV), peste des petits ruminants virus (PPRV), and rinderpest virus (RPV) and forms a group of antigenically related viruses. The viral nucleoprotein (N) is a well-conserved protein among the genus and plays a central role in the replication of the virus. Using a comprehensive approach for siRNA screening of the conserved sequences of the N gene, including sequence analysis and functional in vitro tests, we have identified a region for the design of siRNA effective for the control of PPRV, RPV, and MV replication. Silencing of the N mRNA efficiently shuts down the production of N transcripts, the expression of N protein, and the indirect inhibition of matrix protein, resulting in the inhibition of PPRV progeny by 10,000-fold. These results suggest that siRNA against this region should be further explored as a therapeutic strategy for morbillivirus infections.