The insecticidal activity of a series of 62 plant derived molecules against the chikungunya, dengue and zika vector, the Aedes aegypti (Diptera:Culicidae) mosquito, is subjected to a Quantitative Structure–Activity Relationships (QSAR) analysis. The Replacement Method (RM) variable subset selection technique based on Multivariable Linear Regression (MLR) proves to be successful for exploring 4885 molecular descriptors calculated with Dragon 6. The predictive capability of the obtained models is confirmed through an external test set of compounds, Leave-One-Out (LOO) cross-validation and Y-Randomization. The present study constitutes a first necessary computational step for designing less toxic insecticides. Display omitted •Prediction of the insecticidal activity for sixty-two plant derived compounds against chikungunya and zika A. aegypti vector.•QSAR models are suggested for modelling the acute toxicity of bioactive molecules using 4885 Dragon 6 molecular descriptors.•The Replacement Method based on Multivariable Linear Regression is a reliable feature selection method in QSAR.