Silver nanoparticles (Ag NPs) are extensively used in many industries due to their antimicrobial properties. Their release into aquatic ecosystems has raised concerns about their toxic effects on aquatic organisms. The present study evaluated the toxic effects of Ag NPs on survival rate, bioaccumulation, oxidative stress biomarkers, DNA damage, and histopathology of, Procambarus clarkii. Crayfish was exposed to 0.0, 25, 125 and 250 ppm of Ag NPs for 28 days. Highest mortality (43.3%) was observed at 250 ppm exposure. The rate of bioaccumulation of Ag inside the different tissues increased with increased Ag NPs concentration and time of exposure. Ag NPs-exposed crayfish showed significant increase in the activities of lactate dehydrogenase, lipid peroxidase, catalase, glutathione peroxidase, glutathione S-transferase, gamma-glutamyl transferase, glutathione, metallothioneins, and total lipid in hepatopancreas. Ag NPs also caused an increase in DNA strand breaks. Exposure of the crayfish to Ag NPs caused severe histopathological alterations in both hepatopancreas and gill epithelial cells. In the hepatopancreas, the most notable pathological features included severe tubular degeneration, nuclear pyknosis, and necrotic areas in the digestive tubules. In the gill, the histopathological alterations included swelling of gill lamellae, disorganization and degeneration of epithelial cells. Ultrastructural investigations of hepatopancreas and gills-treated with 250 ppm Ag NPs have been studied. In hepatopancreas, the apical surface of the absorptive cells becomes deformed, swelling mitochondria, and dispersion of Golgi complex, a necrotic nucleus, and ruptured RER. In gills, alterations included presence of degenerated cellular debris and dense granules, decrease in the number of plasma membrane infoldings, and cytoplasmic vacuolation. In conclusion, Ag NPs induced many physiological, histopathological, ultrastructural, and molecular alterations in P. clarkia. Thus, it may be used a bioindicator for Ag NPs toxicity in the aquatic environment. Ag NPs must also be used carefully and their discharge into the aquatic ecosystem should be controlled.