Acute hepatopancreatic necrosis disease (AHPND) is the principal cause of major losses in the penaeid shrimp farm. The disease is associated with intoxication by pirAB toxins homologous with Photorhabdus insecticidal Pir toxin, a protein secreted during bacterial proliferation that affects the epithelial cells of the hepatopancreas. In this study, the progression of AHPND was evaluated by observation of the pathological changes using wet mount analysis, their effect on the hepatosomatic index (HSI) and clinical signs. The wet mount method showed progressive changes, including loss of vacuoles in the epithelial cells, massive sloughing of cells and melanised tubular necrosis, consistent with the histopathological evidence. The effect on clinical signs and HSI in diseased shrimp were significantly different (p < 0.05) concerning the time and healthy shrimp. The HSI values dropped over time, reaching 47% hepatopancreas size in diseased shrimp at 36 hpi, which coincided with the terminal stage. Criteria such as practical scoring system values ≥ 5, pale hepatopancreas without membrane, and massive sloughing of epithelial cells showed high discriminative power to identify diseased shrimp and significant association (p < 0.05) with AHPND. Tubules with deformities and loss of vacuoles in epithelial cells were also criteria with association (p < 0.001) to AHPND, but only in a high degree (G3 deformities) or absence of vacuoles in R and B cells. These criteria can be applied to facilitate AHPND presumptive diagnostic and could be used as screening tools for diagnosis or the surveillance of disease outbreaks in shrimp farms.