This study evaluated the protective effects of silica nanoparticles (SiNPs) derived from melon seed husk ash against the neurotoxic effects of common environmental pollutants, aluminum (Al), nickel (Ni), and their combination in Wistar rats. Ninety-one male Sprague Dawley rats (220–250 g; 6–8 weeks old) were divided into 13 experimental groups. Key findings revealed that exposure to nickel, aluminum, or their combination significantly impaired spatial learning and memory, as evidenced by prolonged latency periods in treated rats. Treatment with SiNPs from melon seed husks reduced these latency periods. Increased Ni and Al levels in the frontal cortex after Ni/Al mixture exposure were mitigated by SiNPs. SiNPs also countered the reduction in iron levels caused by exposure to nickel, aluminum, and the mixture of nickel and aluminum. Moreover, SiNPs ameliorated oxidative stress by reducing MDA levels and increasing antioxidant enzyme activities. SiNPs treatment caused improved nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) levels and reversed elevated Aβ-42 and cyclooxygenase-2 levels, highlighting their potential neuroprotective effects. Our results demonstrated the neuroprotective effects of SiNPs from melon seed husks by attenuating metal-induced oxidative stress and inflammation, though they did not enhance cortical cholinergic activity in rats.