Abstract: Inductively coupled plasma mass spectrometry (ICP-MS), representing one of the most widely used techniques for measuring trace elements in biological samples, has been extensively applied in research on mercury determination. The mercury content in biological samples is generally low, and its determination by ICP-MS is susceptible to tungsten oxides. Consequently, selecting ICP-MS operating parameters directly affects the determination sensitivity, the degree of oxide interference, and, by extension, the quality of analysis results. This study conducted optimization experiments on key ICP-MS operating parameters, including RF power, nebulizer flow, auxiliary flow, sampling depth, and helium flow. Taking the mercury sensitivity and the productivity of tungsten oxides as the main reference indicators, the optimized parameters were determined as follows: RF power of 1 500 W, nebulizer flow of 1.00 L/min, auxiliary flow of 0.7 L/min, sampling depth of 5 mm, and helium flow of 5 mL/min. Comparative analysis revealed that the nebulizer and helium flow had the most significant influence on the analysis results. Based on the determined optimal operating parameters, the method detection limit for mercury was determined to be 0.50×10^-9. The results were consistent with the results verified by several certified reference materials for the biological composition, with the relative standard deviation (RSD, n=10) ranging from 1.03% to 3.14%. This confirms the robustness of the optimized parameters and the applicability of the proposed method in laboratory analysis.