Colorectal cancer (CRC) is one of the most common cancers in the world. When treating patients, therapeutic agents have side effects; hence, the use of natural compounds found in medicinal plants including pomegranate. Ultrasound assisted extraction (UAE) is a new technique evolving to the detriment of traditional methods such as maceration. In this study, we investigated the antioxidant and anticancer effect of pomegranate peel extracts obtained by maceration and UAE at three different ultrasonic power levels (P1 = 10 W; P2 = 50 W; P3 = 100 W) on HCT-116 colorectal cancer cells. Phytochemical screening highlighted the presence of primary and secondary metabolites in pomegranate peels. In addition, the ethanolic extract obtained by UAE at 50 W was shown to be the most concentrated in phenolic and flavonoid compounds and have the most powerful antioxidant activity, which reached a maximum activity of 92% as determined by DPPH test. Similarly, the MTT cell viability test showed that the extract obtained by UAE at 50 W had the most potent inhibitory effect compared to the other extracts. In conclusion, the UAE at 50 W was shown to be the most suitable and efficient extraction technique to obtain bioactive compounds from pomegranate peel extracts that can be used in the treatment of CRC.