Equine Herpesvirus-1 Myeloencephalopathy (EHM) is a highly contagious neurological disease that primarily affects horses but can also affect donkeys and other equids. This study aimed to evaluate clinical, inflammatory, immunological and oxidative stress alterations in donkeys with EHM in Egypt. The study was carried out on 25 clinical cases of donkeys (20 females and 5 males) suffered from signs suggestive for EHM. Five apparently healthy donkeys served as control. All affected donkeys were examined clinically. Nasal swabs were collected from the nasal cavity of all donkeys for molecular diagnosis of EHV-1 using PCR. Serum biochemical analysis was carried out for hepatic functions (ALP, ALT and AST), renal functions (BUN and creatinine), cardiac function (cTnI), inflammatory marker (CRP), immunological markers (IgM, IgG, IgA and IL-6) and oxidative stress markers (CAT, TAC, GSH-Px and MDA). Fever, mild depression and inappetence preceded neurologic signs such as hindlimb weakness, ataxia, urine dribbling, loss of tail tone, recumbency and death. ALP, ALT, AST, BUN, creatinine, and cTnI levels did not show significant differences between donkeys with EHM and control donkeys. Significant increases were noted in IL-6, MDA, IgG, IgM, IgA, and CRP, indicating altered biochemical and immunological responses in the diseased donkeys. It was therefore concluded that EHM in donkeys is associated with significant oxidative stress, immune dysregulation, and CNS damage. Accordingly, targeting inflammatory, immunological and oxidative stress alterations in EHM cases could provide valuable diagnostic approaches to improve the prognosis of the disease.