With the increasing energy demand, fossil fuel depletion rate is increasing, therefore a need to develop sustainable and energy-efficient biodiesel production systems is arising which can compensate for the rate of fossil fuel depletion. The current study aims to analyze biodiesel production from castor oil using a novel hydrodynamic cavitation reactor. Response surface methodology (RSM) coupled with Box-Behnken design was incorporated to carry out the optimization of reaction parameters (reaction temperature, methanol to oil molar ratio, catalyst amount, and reaction time) to obtain desired castor oil methyl ester (COME) yield, functional exergy efficiency (FEE), Universal exergy efficiency (UEE) and normalized exergy destruction (NED). The developed model shows higher goodness of fit with values of R-2 > 99% and R-adj(2) > 98% for all these responses. Desirable reaction conditions for maximum COME yield (92.31 %) were: 57.9 degrees C temperature, 10.3:1 MeOH:Oil molar ratio, 1.05 %wt. catalyst amount and 58.94 min reaction time whereas based on exergetic indicators along with COME yield using multi-response optimization the same were: 60.3 degrees C temperature, 9.82:1 MeOH:Oil molar ratio, 1.06 %wt. catalyst amount and 50.86 min reaction time. The COME yield of 93.83 % and 92.27 +/- 0.43%, FEE of 86.85% and 85.13 +/- 0.40%, UEE of 98.21% and 98.22 +/- 0.18%, NED of 0.14 and 0.13 +/- 0.01 were predicted and experimentally calculated respectively at optimized reaction conditions considering composite desirability of all the responses. Consideration of exergetic indicators in multi-response optimization using RSM resulted in reduction of reaction time and exergy destruction by 14% and 15% respectively.