The uncertainty in determination of nickel in soy milk powder by ultra-wave digestion- inductively coupled plasma mass spectrometry was evaluated and optimized. According to JJF1059.1—2012 Evaluation and expression of uncertainty in measurement and CNAS—GL006: 2019 Guidance on quantifying uncertainty in chemical analysis, the mathematical model of uncertainty evaluation was built. The main sources of uncertainty were analyzed and their uncertainty components were evaluated. Then the relative standard uncertainty and the expanded uncertainty were computed. Finally, the influence of different sources was analyzed and the possible optimization methods for reducing the uncertainty were proposed. When the coverage probability was 95% (i.e., the coverage factor was k=2), the expanded uncertainty of nickel is 0.222 mg/kg, which indicates the determination result of nickel in soy milk powder was (3.825±0.222) mg/kg. The relative uncertainty was reduced from 0.029 0 to 0.023 8 by the optimization methods. Configuration of standard working solution and fitting of standard curve were the main sources of the uncertainty in determination of nickel in soy milk powder by ultra-wave digestion-inductively coupled plasma mass spectrometry, and the optimization could reduce the determination uncertainty significantly.