Manililla is a mango variety whose residues contain bioactive compounds such as polyphenols and flavonoids, with high added value. The use of environmentally friendly extraction technology would be of great relevance; hence, this study aimed to evaluate the effect of solvent relation, sonication time and amplitude on the ultrasound-assisted extraction of total polyphenols in Manililla mango residues (peel, endocarp and kernel) and antioxidant activity. An experimental design 23 with a central point was used to evaluate the curvature behavior of the process variables. Conventional maceration was used as a control. The better conditions were obtained at the central point using 50% ethanol in water, 60% amplitude and 20 min of sonication time. We obtained values of up to 1814 mg GAE/100 g, 469 mg GAE/100 g and 672 mg GAE/100 g of total polyphenols and 1228 mg QE/100 g, 653 mg QE/100 g and 880 mg QE/100 g of total flavonoids for peel, endocarp and kernel, respectively. Mangiferin was quantified in ultrasound-assisted extraction at 150 mg/g in peel and 0.025 mg/g in the kernel, but it was not detectable in maceration. An antioxidant capacity of 87%, 14% and 83% inhibition for peel, endocarp and kernel, respectively, were obtained. Peel and kernel were the residues with higher potential as extraction material, while endocarp was not.