This study aims to develop an optimal continuous process to produce fatty acid methyl esters (biodiesel) from waste cooking oil in a reactive distillation column catalyzed by a heteropolyacid, H3PW12O40·6H2O. The conventional production of biodiesel in the batch reactor has some disadvantage such as excessive alcohol demand, short catalyst life and high production cost. Reactive distillation combines reaction and separation to simplify the process operation. The reaction catalyzed by H3PW12O40·6H2O overcomes the neutralization problem that occurs in conventional transesterification of waste cooking oil with high free fatty acid (FFAs) and water content. Response surface methodology (RSM) based on central composite design (CCD) was used to design the experiment and analyzed four operating parameters: total feed flow, feed temperature, reboiler duty and methanol/oil ratio. The optimum conditions were determined to be 116.23 (mol/h) total feed flow, 29.9 °C feed temperature, 1.3 kW reboiler duty, and 67.9 methanol/oil ratio. The optimum and actual free fatty acid methyl ester (FAME) yield was 93.98% and 93.94%, respectively, which demonstrates that RSM is an accurate method for the current procedure.