Farmed tilapia fish has well recognized potential industries in producing rich proteinous food to reach global population worldwide. Significance of tilapia is relatively resistant to number of diseases and is the second most important group of farmed fish worldwide, with the production of more than 2.5 million tons annually. Unfortunately, mass mortalities of Tilapines were caused by Tilapia lake virus (TiLV) in Israel, Thailand, etc. of around 15 countries including India. In the present study, we had observed vast die-off of tilapia fishes in Katpadi Lake, Vellore, Tamil Nadu, India with the clinical signs of TiLV which includes scale protrusion, swelling of eye balls, reddish skin and abnormalities in swimming behavior. The infected tissue samples of the tilapia were screened against TiLV by Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) and histopathological analysis. RT-PCR results revealed the infection of TiLV in the fishes of Katpadi Lake and histopathological analysis of H & E staining had shown giant cells and multiple nucleic in liver as well as the presence of inclusion bodies. Our diagnostic studies conclude that the suspected fishes of Katpadi Lake were promptly infected with TiLV in farmed fish culture. © 2020 Elsevier Ltd