A novel hybridization of esterification and transesterification processes in a single reactive distillation column was proposed for biodiesel production from waste cooking oil. Continuous process operation was designed in a single reactive distillation column using two different types of heterogeneous catalyst. Amberlyst-15 was loaded on the top of reactive section to eliminate free fatty acid via esterification and CaO/Al2O3 was loaded at the lower section for biodiesel synthesis via transesterification. Suitable design parameters and operating conditions were determined by process simulation using commercial Aspen Plus program. The hybridized process via reactive distillation could reduce the number of equipment, methanol to oil in feed and energy consumption compared to the conventional alkaline catalyzed process and the process of two reactive distillation columns in series (packing with Amberlyst-15 and CaO/Al2O3). Net specific energy requirement was achieved to the lower value as 216 kWhr/kmol biodiesel (or 197 kWhr/kmol biodiesel with allocation to 98% purity of glycerol by-product). This value is lower than that from the conventional process and also the two reactive distillation columns in series of 665 and 224 kWhr/kmol biodiesel, respectively. Moreover, increasing pressure in the hybridized column from 1 to 3 bar decreased the number of reactive stage from 24 stages (4 esterification and 20 transesterification) to 8 stages (3 esterification and 5 transesterification). Several feedstocks with different FFA content can be operated in this hybridization ester- and transesterification column within the 8 reactive stages with flexible of number of catalyst packing stage (acid and alkali catalysts) under column pressure of 3 bar.