In the present work, a new and pioneering hybrid technology, called hydrodynamic-cavitation reactor, was established and investigated to proof the feasibility for the biodiesel production from Chlorella minutissima microalgae. The process parameters such as inlet pressure (A), molar ratio (B), catalyst concentration (C), and reaction time (D) have been investigated over the biodiesel yield from Chlorella minutissima microalgae. Box-Behnken design was applied to develop the second- order polynomial model. The error between experimental values and model prediction was found to be less than 10%. Interactive effects of process variables on the biodiesel yield from Chlorella minutissima microalgae was studied using contour graphs. Inlet pressure of 4 bar, molar ratio of 1: 30, catalyst concentration of 1.3%, and reaction time of 40 min produced 99% of biodiesel yield. Further, a kinetic model has also been developed and considers the transesterification reaction to be a second-order reversible, first order with respect to each of the reactants and products. Estimated values of kinetic constants are k(1) = 0.00014 L min/mol and k(2) = 0.035 L min/mol.