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Spinal cord injury (SCI) is a common devastating condition that causes neuronal loss and dysfunction. Neuroinflammation takes cardinal roles in the pathogenesis of SCI, and nucleotide‐binding domain‐like receptor protein 3 (NLRP3) inflammasome is a mediator of inflammatory reactions occurring in SCI patients. The present study was designed to survey possible relation between thoracic segments whereby injury occurs with the activity of NLRP3 inflammasome complex, and to find the influence of hormonal therapy on the outcomes. Adult male Wistar rats underwent contusion SCI model at three different thoracic segments T1, T6 and T12, then receiving subcutaneous injection of either 10 mg/kg melatonin or 25 μg/kg 17‐β estradiol (E2) every 12 hours until 72 hours post‐SCI. Inflammasome activity was assessed before and at the end of hormonal therapy. SCI rats showed decreased locomotor activity and myelination, and increased activity of the NLRP3, apoptosis‐associated speck‐like protein (ASC) and caspase‐1 at gene and protein levels. Release of interleukins (ILs) 18 and 1β was also augmented after SCI (P < 0.0.5). Hormonal therapy was most effective for targeting mRNA activity at T6 segment. Treatment with either melatonin or E2 caused a decrease in the protein activity of NLRP3 inflammasome at all segments (P < 0.0.5), except for T6 that NLRP3 protein had no response to melatonin. IL‐1β showed decreased activity in response to hormonal therapy at all segments, whilst IL‐18 protein had no change at T1 segment. It is understood that although no alteration in the activity of NLRP3 was found for SCI at different segments, the response to hormonal therapy was influenced by segment. Significance of the study: From our results, the NLRP3 inflammasome activity is not influenced by segment, but there are differences in the effect of hormonal therapy on inflammasome activity at different segments in response to melatonin or E2. These findings also provide the beneficial effects of melatonin or E2 on inflammation caused by spinal cord injury in different thoracic segments. Finally, these data can have therapeutic importance for hormone therapy of spinal cord injury. [ABSTRACT FROM AUTHOR]