By using podophyllotoxin as a phytoinsecticidal lead compound, 15 novel aromatic esters of 4'-demethyl-4-deoxypodophyllotoxin were semisynthesized and preliminarily tested for their insecticidal activity against the pre-third-instar larvae of Mythimna separata Walker in vivo for the first time. Among all of the tested compounds, especially two compounds, 4m and 4o, containing a pyridinyl group, for which final corrected mortality rates against M. separata at 1 mg/mL were 62.9 and 59.2%, respectively, showed the most promising and pronounced insecticidal activity as compared with toosendanin, a commercial insecticide derived from Melia azedarach . The quantitative structure-activity relationships (QSAR) of compounds 4a-4o showed that the relative number of benzene rings and final heat of formation were very important descriptors to their insecticidal activity.