Nowadays, the intensification of the production of biodiesel from non-edible oil crops is mandatory to overcome petrol-fuel depletion and environmental pollution. For the first time, enhanced biodiesel production from castor oil via rotor–stator hydrodynamic cavitation has been studied in this work. Response surface methodology based on one-factor-at-a-time design of experiments was employed for modelling and optimizing the biodiesel yield and the decrease in feedstock viscosity, density, and total acid number (TAN). The predicted optimum parameters of 8.15:1 methanol:oil (M:O), 1499 rpm, 29.38 min, 48.43 °C, and a KOH catalyst concentration of 0.74 wt.% resulted in a 96% biodiesel yield with a concomitant decrease in viscosity, density, and TAN of approximately 95%, 5.12%, and 90.02%, respectively. According to the results of the breakthrough kinetic calculations, the reaction is pseudo-second order, with the activation energy, frequency factor, and reaction rate constant being 0.23 M−1 min−1, 18.77 kJ/mol, and 6.32 M−1 min−1, respectively. The fuel properties of the produced biodiesel and bio-petro-diesel blends were good, comparable to international standards and the marketed Egyptian petro-diesel.