Heavy metal pollution has significant toxicity to plants, so it is necessary to take measures to reduce the toxicity of heavy metals, especially cadmium (Cd). While engineered nanomaterials provide great benefits in environmental remediation, and nano-silicon dioxide (nSiO2) has been considered as a potential new safer agrochemical for establishing plant resistance to Cd stress recently, but the systematically studies remain limited, especially in bitter gourd. The current study was conducted to study the mitigation effects and potential mechanism of exogenous nSiO2 upon Cd toxicity in bitter gourd seedlings. Generally, the application of nSiO2 reduced Cd concentrations in stems and roots. It mitigated Cd-induced root length, plant height, leaf area, and biomass inhibition in all tissues, with the mitigation effect of root length being the most obvious then followed by root dry weight (DW). In addition, exogenous nSiO2 affected the plant mineral elements’ balance, by stimulating leaf/root Zn, leaf/root Na, and Mg content, and depressing Cu, leaf Fe, leaf/root Ca, and stem Na content, in comparison with Cd treatment alone. Moreover, the supplementation of nSiO2 counteracted the changes of certain antioxidase induced by Cd, such as enhanced Cd depressed stem superoxide dismutase (SOD), and stem/root ascorbate peroxidase (APX), meanwhile reduced Cd elevated leaf SOD and peroxidase (POD) activities. In addition, exogenous nSiO2 obviously depressed the accumulation of malondialdehyde (MDA) induced by Cd stress. The results clearly showed that the mitigated Cd toxicity by nSiO2 addition was interrelated to the reduced MDA content and Cd concentration, balanced mineral element content and certain antioxidase activities, suggesting that nSiO2 might play a vital role in providing tolerance against Cd stress in bitter gourd seedlings.