This work developed a facile and environmentally friendly route for lipase-catalyzed synthesis of a hyperbranched polyester by introducing an autocatalytic prepolymerization of comonomers. Trimethylolpropane, 1,8-octanediol, and adipic acid as comonomers for synthesizing the hyperbranched polyester were first prepolymerized via the automatic catalytic effect of the reactants themselves to obtain an appropriate reaction substrate for further lipase-catalyzed polymerization, where immobilized lipase Novozym 435 was used as a biocatalyst. The acidity and fluidity of optimized oligomers after the autocatalytic prepolymerization provide a benign reaction substrate for the retention of enzymatic activity in the subsequent lipase-catalyzed esterification, which is crucial for the enzymatic polymerization. The optimum reaction temperature and reaction time for prepolymerization were determined to be 120 C and 150 min. The molecular weight (M w ) of the prepared polyester was approximately 26,300 g/mol. Quantitative analysis of 1 H-NMR and inverse-gated 13 C-NMR spectra confirmed the hyperbranched structure of the resulting polyester with a branching degree of 31.3%.