Microencapsulation of bioactive compounds (BC) from rambutan peel by spray drying using DE10 maltodextrin as encapsulating agent was performed. The optimal conditions for the ethanolic extraction of BC were 60 °C, with a time of 1 h, 55% aqueous ethanol and three extraction cycles. The best spray drying encapsulating conditions for BC and antioxidant capacity (AC) were: inlet temperature 160 °C, outlet temperature 80 °C, and 10% encapsulating agent concentration in the feeding solution (core:encapsulating agent ratio of 1:4). With these conditions, retention and encapsulation efficiencies obtained were higher than 85%, the water activity value, moisture content and Hausner Index were of 0.25 ± 0.01, 3.95 ± 0.10%, and 1.42 ± 0.00, respectively. The optimized powder presented good solubility and morphological properties, showing microcapsules without ruptures. Based on these results, microencapsulation by spray drying is a viable technique which protects BC of rambutan peel, facilitating its application in the food, pharmaceutical, and cosmetic industries.