A mortality event of catfish (Pangasius sp.) occurred on a farm at Lebak Regency from the end of 2021 until early 2022 with 90-120g weight of fish. Histopathological sampling was conducted three times at one-week intervals to investigate the cause of mortality and monitor the factors influencing disease progression. During the mortality period, the fish became lethargy and had less appetite. Petechial hemorrhages were observed in the head area, around the mouth, fins, ventral abdomen, and body surface. The liver appeared pale with small white nodules, which were also found in the spleen and kidney. These clinical signs persisted until the last sampling. In bacteriological examination, Aeromonas sobria and Edwardsiella ictaluri were isolated from the liver, spleen, and kidney. The histopathological changes observed during this mortality event were associated with a mixed infection of bacteria, parasites, and water quality alterations. Fish had bacterial necrosis with leukocyte infiltration in the liver, spleen, kidney, and heart in the first and second samplings. At the end of the organ examination, bacterial colonies no longer existed and the feature indicated a chronic condition. The gill tissues showed parasitic branchitis and circulatory disturbances until the end of sampling, which is related to poor water quality. Effective water quality management is important for preventing disease development and supporting the success of fish farming.