Novel diagnostic and therapeutic methods were utilized in the successful management of severe elephant endotheliotropic herpesvirus hemorrhagic disease (EEHV-HD) in a 1.9-yr-old captive Asian elephant (Elephas maximus). High levels of EEHV1A viremia were detected for 12 d. In addition to established EEHV treatments, therapies included famciclovir-fortified elephant whole blood and plasma, mesenchymal stem cells harvested from elephant umbilical tissue, and aminocaproic acid. Testing conducted to examine the effects of EEHV infection on hemostasis suggested marked intravascular coagulation with decreased plasminogen activity and increased D-dimer concentrations. Thromboelastography was used to assess the efficacy of aminocaproic acid and demonstrated hypofibrinolysis on samples taken after drug administration, as compared with samples from healthy adult Asian elephants. A serological assay for a novel EEHV1A-specific antibody marker (E52) was developed due to lack of seroconversion to a previously established EEHV1A-specific antibody marker (ORFQ) and showed a sustained increase after EEHV-HD illness.