Mango is attracting increasing global attention for its superior flavor and nutritional benefits. However, the use of pesticides has resulted in a threat to its quality, safety, and human health due to their inevitable residue. There is an urgent need for advanced technologies that can efficiently and sensitively analyze a wide range of pesticides. In this study, a high-throughput screening and quantification method for 345 pesticides in mango was established by applying a modified QuEChERS method combined with liquid chromatography-quadrupole-time-of-flight mass spectrometry (LC-Q-TOF/MS). A response surface methodology (RSM) optimized the critical parameters for extracting various pesticides in 1% acetic acid-acetonitrile (v/v) using MgSO4, PSA, C18, and GCB as the adsorbents. The proposed method was successfully validated and applied to the quantitative detection of pesticide residues in 73 mango samples from Hainan. The study found pesticide residues in 95.9% of mango samples, of which 3 samples had residue concentrations in excess of the Chinese maximum residue limit. A total of 24 pesticides were detected, with detection percentages ranging from 1.4% (Thiabendazole) to 41.1% (Pyraclostrobin). Considering the possible health risks related to pesticide residues, risk assessment of human exposure to pesticides via intake of mango was evaluated. The acute and chronic dietary exposure risks related to pesticide residues in mango were accepted. In conclusion, this study provides a powerful platform for monitoring multiple pesticides in mango. First, it can promote the rational use of pesticides, and second, it can help consumers to assess the risk of dietary exposure to pesticide residues.