Background: Septicemic salmonellosis caused by host-adapted strains, particularly Salmonella Dublin, is a leading cause of sudden death in post-weaning calves in industrial dairy farms. Empirical and early antibiotic treatment prior to sampling typically results in false-negative bacterial cultures and diagnostic confusion. Objectives: The objective of this study was to investigate a severe septicemic outbreak in weaned calves and to compare the diagnostic value of histopathology and microbial culture under routine conditions at dairy farms. Methods: A descriptive-analytical study was conducted in June 2025 following acute mortalities in 70-to-80-day-old calves at a large industrial farm in Neyshabur. Detailed clinical examinations and necropsy were performed. Samples of the liver, spleen, lung, and mesenteric lymph nodes were simultaneously collected for bacterial culture, histopathological examination, and clinical pathology analysis (including complete blood count and serum biochemistry). Results: Affected calves displayed severe fever, diarrhea, marked icterus, respiratory distress, joint swelling, and neurological signs. Mortality in symptomatic cases exceeded 60% and often occurred in less than 48 hours. Bacterial culture of all samples was negative. However, histopathology confirmed distinct paratyphoid nodules with hepatocyte necrosis in the liver, severe interstitial pneumonia, and septic emboli. Furthermore, laboratory results showed severe leukocytosis with a left shift and toxic changes, a significant increase in fibrinogen, and cholestatic liver enzymes such as GGT and bilirubin, all confirming active septicemia with severe hepato-biliary damage. Conclusions: In calves that have received antibiotics prior to sampling, histopathology and clinical pathology profiles represent the gold standard for diagnosing septicemic salmonellosis, definitively surpassing microbial culture. The simultaneous occurrence of icterus, elevated GGT, interstitial pneumonia, and paratyphoid nodules creates a very high suspicion for Salmonella Dublin. Sustainable disease control requires regular serological screening of the dam herd, removal of carrier cows, and rigorous management of colostrum and waste milk.

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