Drought is one of the non-biological stresses that affect the growth and development of plants globally, especially Lagenaria siceraria plants. As a common nitric oxide (NO) donor, sodium nitroprusside plays a significant role in enhancing the resistance of plants to non-biological stresses. In this study, ‘Yayao’ (L. siceraria) was selected as the material through which to investigate the mitigating effects of different concentrations of sodium nitroprusside on L. siceraria plants under moderate drought stress. The results showed that a concentration of 0.25 mmol·L−1 sodium nitroprusside had the best mitigation effect on drought stress in L. siceraria plants. Under this condition, the plant height and leaf dry weight and fresh weight increased by 12.21%, 21.84%, and 40.48%. The photosynthetic parameters were significantly improved, and the fluorescence parameters Fo and Fm were reduced by 17.04% and 7.80%, respectively. The contents of soluble sugar and proline increased by 35.12% and 44.49%, respectively. The activities of superoxide dismutase (SOD), catalase (CAT), and peroxidase (POD) increased by 51.52%, 164.11%, and 461.49%, respectively. The content of malondialdehyde (MDA) decreased by 34.53%, which alleviated the damage caused by reactive oxygen species. Additionally, sodium nitroprusside promoted the expression of genes related to antioxidant enzymes (SOD, CAT, and POD). Overall, this analysis indicates that an appropriate concentration of sodium nitroprusside can enhance the drought tolerance of L. siceraria plants through multiple aspects and alleviate the harm caused by drought stress.