The present study aimed to investigate the clinical blood gas indices and histopathological consequences after intrathecal injection of tolfenamic acid and lidocaine Hcl and moreover, to elucidate the spinal safety of tolfenamic acid as a cyclooxygenase inhibitor in donkeys. Ten clinically healthy donkeys were divided into two groups, 5 animals each. The first group received lidocaine Hcl 2% and the second one received tolfenamic acid 4% intrathecally. The physical parameters and ataxia, analgesia, and motor blockade scores were recorded. Blood gases and acid base balance indices and histopathological examination were done. Blood pH level was significantly decreased (P < 0.05) and the blood pCO2 level was significantly increased (P < 0.05) 15 min after intrathecal injection of tolfenamic acid. Additionally, there was a significant difference in the motor block scores between the two groups at 2 and 4 h post-injection. Histopathological findings of the spinal cord of tolfenamic acid–injected group revealed neurodegeneration and necrosis which were manifested clinically by paraplegia. In conclusion, the present study uncovered the analgesic and motor effects of commercially prepared tolfenamic acid following intrathecal injection in donkeys. Nevertheless, it is unsafe because of its neurotoxic effect on the spinal cord which was manifested clinically by paraplegia of donkeys. On the other hand, intrathecal administration of lidocaine Hcl was safe and causes nonserious cardiopulmonary changes.