The bioethanol production from industrial residues is acquiring attraction as a strategy for increasing energy security. The aim of present study is to optimize the production of bioethanol from cassava peel using statistical experimental design. The total carbohydrate content of about 90% in cassava peel was subjected to enzymatic liquefaction followed by simultaneous saccharification and fermentation (SSF) for ethanol production. Based on Plackett–Burman design, three factors viz., substrate concentration (10–70 g/L), α‐amylase concentration (5–25% [v/v]) and SSF mixture containing glucoamylase and Zymomonas mobilis (5.15%–25.75% [v/v]) were found to have significant effect among 11 factors selected for screening. These factors were optimized by Box–Behnken design to yield second order polynomial model. The ethanol concentration increased significantly from 4.25 to 33.17 g/L with increase in substrate concentration from 10 to 70 g/L. The maximum ethanol concentration obtained under optimum conditions of 69.82 g/L substrate concentration, 24.74% (v/v) α‐amylase concentration and 5.22% (v/v) SSF mixture were 35.018 and 35.010 g/L (83% yield) based on mathematical model and experiments, respectively. The results indicate cassava peel could serve as a potential substrate for ethanol production and the ability of the statistical modeling for the optimization of process conditions was also confirmed. © 2014 American Institute of Chemical Engineers Environ Prog, 34: 567–574, 2015