Nyamplung (Calophyllum inophyllum Linn) is one of the most widely grown plants in Indonesia. In addition, nyamplung oil has a future competitive advantage in that it can be processed into biodiesel. However, conventional methods for transesterification of nyamplung oil have been less effective. Therefore, in this study biodiesel was produced using microwaves as one of the alternative methods that can improve the shortcomings of conventional methods. In addition, optimization of parameters such as microwave power, catalyst concentration and transesterification time was done using Box-Behnken design. The combination of microwave with CaO catalyst and treated with Box-Behnken design are considered as a new and modern method for production of biodiesel from nyamplung oil and optimizing the factors that affected the transesterification process. The results showed that factors such as microwave power of 449.29W, concentration of catalyst of 4.86% and transesterification time of 10.07 min can produce optimal yield of biodiesel of 92.73% with reliability of 93.22%.