Osmotic distillation (OD) was implemented at laboratory scale to concentrate a red fruit juice produced from a blend of blood orange, prickly pear, and pomegranate juice. The raw juice was clarified by microfiltration and then concentrated by using an OD plant equipped with a hollow fiber membrane contactor. The clarified juice was recirculated on the shell side of the membrane module, while calcium chloride dehydrate solutions, used as extraction brine, were recirculated on the lumen side in a counter-current mode. The influence of different process parameters, such as brine concentration (20, 40, and 60%w/w), juice flow rate (0.3, 2.0, and 3.7 L min−1), and brine flow rate (0.3, 2.0, and 3.7 L min−1) on the performance of the OD process in terms of evaporation flux and increase in juice concentration, was investigated according to the response surface methodology (RSM). From the regression analysis, the evaporation flux and juice concentration rate were expressed with quadratic equations of juice and brine flow rates, as well as the brine concentration. The desirability function approach was applied to analyse the regression model equations in order to maximize the evaporation flux and juice concentration rate. The optimal operating conditions were found to be 3.32 L min−1brine flow rate, 3.32 L min−1juice flow rate, and an initial brine concentration of 60%w/w. Under these conditions, the average evaporation flux and the increase in the soluble solid content of the juice resulted in 0.41 kg m−2h−1and 12.0 °Brix, respectively. Experimental data on evaporation flux and juice concentration, obtained in optimized operating conditions, resulted in good agreement with the predicted values of the regression model.