Caseous lymphadenitis is a chronic disease of sheep and goats that causes significant breeding and economic losses. The aim of the study was to assess the differences in gene activity (expression) in resistant and diseased sheep by high-throughput sequencing. A total of 440 differentially expressed genes were detected in both groups compared to healthy ewes. The disease significantly affected the metabolic activity of cells, the cell cycle, including DNA replication, and energy metabolism. Inflammation mediated by chemokine and cytokine signaling pathway, which modulates and controls the development of the anti-inflammatory response, was the most activated.