A fast method was developed for the determination of a novel insecticide (flupyradifurone) in fruits and vegetables using QuEChERS combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS). By analyzing the matrix interferents in the sample extraction purification solution, the combination of dispersed adsorbents was optimized. Using 1:2 diluted sample solution could effectively reduce or eliminate the matrix effects, and the external standard method of solvent standard solution could be directly used for quantitative analysis, without the need to use matrix-matched standard solution or isotope internal standard to compensate the matrix effects. Using the optimized method, the recoveries at fortification levels of 4, 8, and 40 μg/kg in apples, oranges, tomatoes, spinach, sweet corn and green soybeans ranged from 80.90% to 100.15% with relative standard deviations of 3.56% to 12.88%. The limits of quantification (S/N > 10) were 4 μg/kg, and the absolute matrix effects of all matrices was below 10%. The method has been shown to be sensitive, simple, accurate, and suitable for the rapid determination of flupyradifurone in fruits and vegetables and to be a methodological approach for the minimization of matrix effects in LC-MS/MS quantitative analysis.