Ethyl levulinate has been considered as a potential liquid biofuel candidate for the future. The conversion of glucose to ethyl levulinate in ethanol medium was firstly investigated in this study. Experimental results showed that the combination of extremely low sulfuric acid and zeolite USY can be used as an effective catalytic system for one-pot EL production from glucose. The ethyl levulinate yield of 51.47% from glucose can be obtained at 180°C and 120min in the mixed acid system comprising of 0.1% sulfuric acid and 2.0% USY. Furfural residues were further taken as substrates for ethyl levulinate production in the mixed acid system. Artificial neural network coupled with genetic algorithm was employed to optimize the process. The optimum conditions were reaction temperature 219°C, USY loading 2.3%, mass ratio of liquid to solid 40 and reaction time 107min. Under the optimum conditions, higher ethyl levulinate yield of 18.68% was obtained, representing a theoretical yield of 51.22%.