This study investigates and models the grinding process of single crystal sapphire. Five parameters: the wheel speed, the feed speed, the vertical feed, the ultrasonic assistance and the crystallographic direction were considered via a design of experiments (DoE) approach. The responses were multiple but can be divided in three groups: the process, the machine and the grinding quality. DoE results revealed that the parameters interact in a complex manner and depends on the responses. Therefore, to gain a better understanding of the grinding process of sapphire, the interactions between parameters have also to be taken into consideration. It was found that three main parameters have the largest influences on the tangential grinding forces: the wheel speed, the feed speed and the vertical feed. In contrast, the median defect area is mainly impacted by the quadratic effects of the wheel speed and vertical feed followed by various interactions. After an optimization procedure, the second optimum for the tangential forces was found to be very close to the best optimum for the median defect area. The optimum solution is: a wheel speed of 7'500 rpm, a feed speed of 60 mm∕min, a vertical feed of 12.5 μm∕pass, no ultrasonic assistance and grinding along the c-axis. This set of parameters was validated with additional and repeated tests on both Verneuil and Kyropouloas sapphire. Finally, it came out that the optimum solution has also a very good productivity.