Barley straw is a lignocellulosic biomass that can be used to obtain value-added products for industrial applications. Barley straw hydrolysis with sodium sulfite facilitates the production of lignosulfonates. In this work, the delignification process of barley straw by solubilizing lignin through sulfite method was studied. Response surface methodology and artificial neural network were used to develop predictive models for simulation and optimization of delignification process of barley straw. The influence of parameters over sulfite concentration (1.0 to 10.0%), particle size (8 to 20), and reaction time (30 to 90 min) on total percentage of solubilized material was investigated through a three level three factor (33) full factorial central composite design with the help of Matlab® ver. 8.1. The results show that particle size and sulfite concentration have the most significant effect on delignification process. Both techniques, response surface methodology and artificial neural networks, predicted the lignosulfonate yield adequately, although the artificial neural network technique produced a better fit (R2 = 0.9825) against the response surface methodology (R2 = 0.9290). Based on these findings, this study can be used as a guide to forecast the potential production of lignosulfonates from barley straw using different experimental conditions.