Peste des petits ruminants (PPR) is an acute and fatal contagious disease, caused by the PPR virus (PPRV), and is one of the most damaging animal diseases. The replication of many viruses is closely related to the regulation of histone deacetylases (HDACs). TMP269, a selective class IIa HDAC inhibitor, plays an important role in cancer therapy and also modulates viral replication. However, the regulatory effects of TMP269 on PPRV replication remain poorly understood. In this study, we employed western blotting, quantitative Real-time PCR (qRT-PCR), RNA sequencing (RNA-seq), and enzyme-linked immunosorbent assay (ELISA) to evaluate the inhibitory and anti-inflammatory effects of TMP269 on PPRV replication. Western blot analysis showed that TMP269 treatment significantly suppressed PPRV replication in Vero and caprine endometrial epithelial cells (EECs). RNA-seq data revealed that the upregulation of inflammatory response genes induced by PPRV infection was markedly reversed by TMP269. Further, qRT-PCR and ELISA demonstrated that TMP269 decreased the expression of the pro-inflammatory chemokines CCL2, CCL5, CCL7, CXCL8, and cytokine IL-6 during infection, suggesting the vital role of TMP269 in anti-inflammatory processes. Collectively, our findings suggest that the class IIa HDAC inhibitor TMP269 is a promising antiviral agent for PPRV and provides novel insights into the antiviral and anti-inflammatory abilities of TMP269.