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Spinal cord injury (SCI) triggers secondary neuroinflammatory and inflammasome-associated responses that contribute to tissue damage and functional impairment. This study evaluated nanocurcumin in experimental SCI using integrated experimental, computational, and exploratory machine-learning approaches. Adult male Wistar rats were allocated to Sham, SCI, or SCI + nanocurcumin groups. SCI was induced by T6 contusion, and nanocurcumin (50 mg/kg, intraperitoneally) was administered every 12 hours for 72 hours. Functional, histological, molecular, and inflammatory outcomes were assessed using BBB scoring, Luxol Fast Blue staining, immunofluorescence, RT-qPCR, and ELISA. SCI impaired locomotor function and myelin integrity and increased inflammasome-associated and inflammatory markers. Nanocurcumin significantly improved BBB scores, increased the LFB-positive myelinated area, and attenuated these molecular alterations. Tissue IL-1β, IL-18, HMGB1, and TLR4 levels were also reduced following nanocurcumin treatment compared with untreated SCI. Correlation and hierarchical clustering analyses demonstrated coordinated molecular-functional associations and separation of SCI from control and treated profiles. Exploratory Random Forest/SHAP analyses highlighted NF-κB, Caspase-1, NOX2, and NLRP3 as influential variables for group discrimination. Docking predicted favorable curcumin-target interactions, while MD simulations supported distinct conformational behavior of selected complexes. Overall, nanocurcumin was associated with attenuated inflammatory and inflammasome-associated responses and improved early functional and histological outcomes following SCI.