The  objective of this study was to  maximize production of pyocyanin by Pseudomonas  aeruginosa RS11using response surface methodology. Plackett-Burman design (PBD) was used to select the operational parameters influencing the optimization process. The most effective variables (pH, yeast extract, and K2SO4) were chosen for further optimization using Box-Behnken design. The optimal fermentation parameters for  enhancing PYO production were found to be pH 5.8, K2SO4 20 g/l and yeast extract 1.5 g/l. The model predicted a  PYO yield of  15.55 µg/ml.  Verification of the optimization showed that the maximum PYO yield reached 17.7 µg/ml. Up to our knowledge, this is the first report on PYO optimization by Pseudomonas  aeruginosa RS11 using response surface methodology. The yield after optimization was 2.1-fold higher than the unoptimized medium. The response surface methodology (RSM) with the Box–Behnken design was a useful tool for achieving the high yield of pyocyanin by Pseudomonas  aeruginosa RS11.