As a major by-product of dragon fruit, dragon fruit peel (DFP), whether freshly consumed or processed, is typically dumped into the ecosystem. This causes environmental pollution and wastes the bioactive compounds in the peel. Phenolic compounds are one of the bioactive compounds in DFP with multiple functions, such as helping to prevent brain function deterioration, arthritis, cholesterol elevation, and other major diseases. The extraction of phenolic compounds from DFP is a key step in the isolation and identification of phytochemicals in plant materials. Among the various extraction methods, ultrasonic-assisted extraction (UAE) is considered a promising method for the extraction of polyphenols from fruits due to its advantages of high repeatability, short processing time, and low cost. The main objective of the extraction process is to maximize the yield of the specified ingredient under conditions of high purity without affecting the properties of the extracted ingredient, and it is necessary to optimize the factors affecting the extraction. Therefore, the purpose of this chapter is to provide a detailed description of the abovementioned optimization operations, including specific factors that affect extraction, such as solvent concentration, liquid-to-solid ratio, ultrasonic extraction time, ultrasonic power, and ultrasonic temperature.