Multiple players are involved in motor and sensory dysfunctions after spinal cord injury (SCI). Therefore, therapeutic approaches targeting these various players in the damage cascade hold considerable promise for the treatment of traumatic spinal cord injury. Soluble epoxide hydrolase (sEH) is an endogenous key enzyme in the metabolic conversion and degradation of P450 eicosanoids called epoxyeicosatrienoic acids (EETs). sEH inhibition has been shown to provide neuroprotective effects upon multiple elements of neurovascular unit under cerebral ischemia. However, its role in the pathological process after SCI remains unclear. In this study, we tested the hypothesis that sEH inhibition may have therapeutic effects in preventing secondary damage in rats after traumatic SCI. sEH was widely expressed in spinal cord tissue, mainly confined to astrocytes, and neurons. Administration of sEH inhibitor AUDA significantly suppressed local inflammatory responses as indicated by the reduced microglia activation and IL-1 beta expression, as well as the decreased infiltration of neutrophils and T lymphocytes. Meanwhile, reactive astrogliosis was remarkably attenuated. Furthermore, treatment of AUDA improved angiogenesis, inhibited neuron cells apoptosis, alleviated demyelination and formation of cavity and improved motor recovery. Together, these results provide the first in vivo evidence that sEH inhibition could exert multiple targets protective effects after SCI in rats. sEH may thereby serve as a promising multi-mechanism therapeutic target for the treatment of SCI.