In this study, exergoeconomic and exergoenvironmental approaches were applied to evaluate and optimize the performance of a low-energy consumption, high frequency piezoelectric ultrasonic reactor used to synthesize biodiesel from waste cooking oil (WCO). The effects of various process parameters viz. methanol/oil molar ratio (X), transesterification temperature (T), and residence time (t) on the exergoeconomic and exergoenvironmental variables were comprehensively assessed and discussed. The exergoeconomic and exergoenvironmental variables were cost and environmental impact per unit of exergy for the product, relative cost and environmental impact differences, cost and environmental impact associated with exergy destruction, and exergoeconomic and exergoenvironmental factors. An optimization study was also carried out using a coupled scheme of adaptive network-based fuzzy inference system (ANFIS) and non-dominated sorting genetic algorithm-II (NSGA-II). Two more relevant exergy-based variables, i.e., cost and environmental per unit of exergy for the product as objective functions were modeled using the ANFIS approach on the basis of process parameters. The process yield as a threshold function was similarly simulated using the ANFIS approach. The optimum operating conditions of the system were then explored by NSGA-II algorithm through minimizing both objective functions while complying with the ASTM standard on process yield (i.e., conversion efficiency > 96.5%). Overall, the process parameters profoundly affected the exergoeconomic and exergoenvironmental variables. Results indicated that the ANFIS approach accurately predicted the objective and threshold functions with an R-2 > 0.99. The optimum operating conditions were: X = 7.4, T = 60 degrees C, and t = 10 min. Under these conditions, the cost and environmental impact per unit of exergy for the product were respectively found to be 2.23 USD/GJ and 1.32 mPts/GJ, whereas the process yield stood at 96.5% meeting the ASTM standard. In general, exergoeconomic and exergoenvironmental approaches appeared to be promising complements to the conventional exergy analysis for developing thermodynamically, economically, and environmentally conscious biodiesel production systems.