Nile tilapia (Oreochromis niloticus) is one of the most important aquaculture species farmed worldwide. However, the recent emergence of tilapia lake virus (TiLV) disease, also known as syncytial hepatitis of tilapia, has threatened the global tilapia industry. To gain more insight regarding the host response against the disease, the transcriptional profiles of liver in experimentally-infected and control tilapia were compared. Analysis of RNASeq data identified 4640 differentially expressed genes (DEGs), which were involved among others in antigenprocessing and presentation, MAPK, apoptosis, necroptosis, chemokine signaling, interferon, NF-kB, acute phaseresponse and JAK-STAT pathways. Enhanced expression of most of the DEGs in the above pathways suggests anattempt by tilapia to resist TiLV infection. However, upregulation of some of the key genes such as BCL2L1 inapoptosis pathway; NFKBIA in NF-kB pathway; TRFC in acute phase response; and SOCS, EPOR, PI3K and AKT inJAK-STAT pathway and downregulation of the genes, namely MAP3K7 in MAPK pathway; IFIT1 in interferon;and TRIM25 in NF-kB pathway suggested that TiLV was able to subvert the host immune response to successfullyestablish the infection. The study offers novel insights into the cellular functions that are affected following TiLVinfection and will serve as a valuable genomic resource towards our understanding of susceptibility of tilapia toTiLV infection.