ABSTRACT Polyesters are polymers of choice in the design of drug delivery systems as a result of their good biocompatibility and their (bio)degradability. Such polyesters are mainly obtained by polymerization techniques using chemically based initiators whose presence in the final materials, even at trace levels, might induce toxic effects on in vivo uses. Therefore, lipases‐catalyzed ring opening polymerization (ROP) of lactones might be considered as interesting solutions. In this context, we have studied the possibilities to use lipase‐catalyzed ROP of the benzyl malolactonate (MLABe) to obtain the poly(benzyl malate), PMLABe. A Design of Experiment (DoE) approach has been elaborated to identify the important parameters having a significant influence on the polymerization reaction and on the characteristics of the obtained PMLABe. Such DoE technique allowed us to select conditions for lipase‐catalyzed ROP of MLABe leading to PMLABe with a mass‐average molar mass of around 10,000 g/mol with a dispersity of 1.4. © 2016 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2017, 134, 44604.