The Morbillivirus genus includes measles virus (MV), peste des petits ruminants virus (PPRV) and rinderpest virus (RPV). Although preventive vaccines are available against these three viruses, efficient therapeutics for virus control under emergency situations are desirable. Inhibition of morbillivirus replication can be achieved by post-transcriptional silencing of the nucleoprotein (N) gene by RNA interference (RNAi). The viral N protein, a well conserved protein among the genus, plays a central role in the replication of the virus. Using a comprehensive siRNA-based screening of the conserved sequences of the N gene, we have identified, three common positions on the N gene, for the design of siRNA evenly effectives for PPRV, RPV and MV. siRNA silencing resulted in more than 80% decrease of the viral replication in infected Vero cell, as shown by real-time quantitative PCR, flow cytometry and virus titration. In a second step, a recombinant replication-defective human type 5 adenovirus (Ad-5) encoding one of the functional sequences directed against the N gene of PPRV was constructed and shown to reduce the PPRV replication in vitro. These results illustrate that adenovirus vector could be a promising candidate for the development of siRNA antiviral treatments against morbilliviruses.