Experiments were conducted to evaluate the role of exogenously applied nitric oxide (NO; 50 µM) and spermidine (Spd; 100 µM) in alleviating the damaging effects of Ni (1 mM NiSO46H2O) toxicity on the growth, chlorophyll metabolism, photosynthesis, and mineral content in tomato. Ni treatment significantly reduced the plant height, dry mass, and the contents of glutamate 1-semialdehyde, δ-amino levulinic acid, prototoporphyrin IX, Mg–prototoporphyrin IX, total chlorophyll, and carotenoids; however, the application of NO and Spd alleviated the decline considerably. Supplementation of NO and Spd mitigated the Ni-induced decline in photosynthesis, gas exchange, and chlorophyll fluorescence parameters. Ni caused oxidative damage, while the application of NO, Spd, and NO+Spd significantly reduced the oxidative stress parameters under normal and Ni toxicity. The application of NO and Spd enhanced the function of the antioxidant system and upregulated the activity of glyoxalase enzymes, reflecting significant reduction of the oxidative effects and methylglyoxal accumulation. Tolerance against Ni was further strengthened by the accumulation of proline and glycine betaine due to NO and Spd application. The decrease in the uptake of essential mineral elements such as N, P, K, and Mg was alleviated by NO and Spd. Hence, individual and combined supplementation of NO and Spd effectively alleviates the damaging effects of Ni on tomato.