One adult leopard (Panthera pardus) and five adult tigers (Panthera tigris) presented with a range of nonspecific clinical signs, including lethargy (6/6), mobility deficits (4/6), and hyporexia (3/6). Hematology and biochemistry revealed a hyperproteinemia characterized by hyperglobulinemia (4/6), hepatocellular enzyme activity increases (3/6), azotemia (3/6), leukocytosis (2/6), hyperbilirubinemia (2/6), or a combination of conditions. Further diagnostics and management varied with the presenting signs and clinicopathological findings, including supportive care, diagnostic imaging, and blastomyces urine antigen analyses. Two animals died, and four were euthanatized. Postmortem findings included granulomatous pneumonia (6/6), fibrinous pleural effusion (3/ 6), pericardial effusion (2/6), and diffuse icterus (1/6). Histopathology revealed round to oval structures with a thin clear wall and purple inclusions within cells of the mononuclear phagocyte system, consistent with Histoplasma capsulatum, in each animal. Disseminated histoplasmosis was found in five cases, with organisms present in the lung (5/5), liver (3/5), lymph nodes (3/5), spleen (2/5), bone marrow (2/5), thyroid (1/5), tongue (1/ 5), kidney (1/5), or a combination of organs. One tiger was found to have pulmonary histoplasmosis without evidence of disseminated infection. On the basis of clinical and pathological findings, histoplasmosis was diagnosed. This case series illustrates the difficulties in antemortem diagnosis of histoplasmosis on the basis of complete blood count, serum biochemistry profile, and antigen testing and underscores that histoplasmosis should be considered a differential diagnosis in any felid presenting with nonspecific clinical signs in endemic areas.