Previous studies have focused on long-term dietary supplementation of fish with the diatom Amphora coffeaeformis to prevent infections. This study introduces a novel approach by assessing short-term post-infection administration of A. coffeaeformis to mitigate Aeromonas sobria infection in Nile tilapia (Oreochromis niloticus). This approach addresses the need for sustainable strategies to manage infections after onset, reducing reliance on antibiotics. The effects of A. coffeaeformis on hepatic-renal function, antioxidant-immune response, and histopathological alterations were evaluated. Two hundred and ten O. niloticus were distributed into seven groups. The first group (CONT) was injected intraperitoneally with sterile tryptic soy broth (0.2 mL) and fed a basic diet. The remaining six groups were injected with A. sobria (1.5 x 10⁷ CFU, 0.2 mL) and fed a control-based diet until clinical signs appeared. Subsequently, the second group (I) fed a basic diet. The third (I+AMP50) and fourth (I+AMP70) received diets containing A. coffeaeformis powder at 50 or 70 g kg- 1, respectively. The fifth (I+AME50) and sixth (I+AME70) groups received diets containing 50 or 70 g kg- 1 of A. coffeaeformis extract, while the seventh group (I+OXY) received 500 mg kg- 1 of oxytetracycline. The infected fish treated with A. coffeaeformis extract, particularly at 70 g kg- 1 (AME70), exhibited significantly improved hematological and histopathological profiles, as well as improved liver and kidney function, antioxidant responses, and immune responses. This study highlights the potential of short-term post-infection supplementation with A. coffeaeformis,