Background: Although the powerful scientific studies discover Cucurbita pepo probable in the treatment of various ailments, Cucurbita pepo being employed as food material in various part of the world, there is indeterminate in the neuroprotective potential of Cucurbita pepo in LPS induced neuroinflammation experimental model. Aim and Objectives: This study is intended to examine the protective effect of Cucurbita pepo against LPS induced neuro-inflammation in C57BL/6 mice. Materials and Methods: A single dose intraperitoneal (i.p) injection of lipopolysaccharide liquefied in saline was given to C57BL/6 mice. (n=10 per group). Aqueous extract of Cucurbita pepo (AECP) at a concentration of (100 mg/kg b.w.) was administered orally to C57BL/6 mice 1 hour before LPS induction (7 days) and continuous till 30 days (n=10 per group). Results: Levels of enzymatic antioxidants such as catalase (43.26±4.61 %) and superoxide dismutase (43.16±3.82%) restored decidedly and non-enzymatic antioxidants GPx and GSH restored up to 20.81±4.22 and 58.28±2.44 percentage respectively upon AECP treatment. Oxidative stress markers NO and LPO abridged to 57.64±3.17 and 53.25±2.53 percentage compared to LPS induction group. AECP treatment lessened the protein expression level of proinflammatory cytokines Tumor Necrosis Factor-α (TNF-α), Interleukin 1 beta (IL1-β) and Interleukin 6 (IL-6) significantly (P < 0.05) detected by ELISA. Signs of prolong inflammation caused higher expression of isoforms of nitric oxide synthases genes (eNOS, nNOS and iNOS) signifies NO productivity. In the cortex of LPS challenged mice, AECP significantly (P <0.05) condensed the LPS persuaded expressions of eNOS (1.98±0.41 fold), nNOS (1.74±0.26 fold) and iNOS (1.81±0.52 fold) genes. Also, oral administration of AECP significantly (P < 0.05) reduced the expression of ionized calcium binding adaptor molecule (Iba-1) in LPS induced mice brain cortex (30.37%), were additional supports the anti-inflammatory potential of AECP. Conclusion: In summary AECP displays antioxidant and anti-inflammatory potential against LPS induced neuroinflammation. However, the mechanistic insights of Cucurbita pepo in neuroprotection potential have explained in detail.