Therapeutically important bioactive polyphenols were efficiently extracted from Garcinia indica using ultrasound-assisted extraction (UAE) technique and investigated for its antioxidant and anticancer activities. Response surface methodology-based central composite face-centered experimental design and adaptive neuro-fuzzy inference system were efficiently applied to optimize the effect of UAE parameters for maximum recovery of bioactive polyphenols. The effect of process depending on variables such as ultrasound intensity (X1), methanol concentration (X2), pulse cycle (X3), particle size (X4) and temperature (X5) was studied to obtain highest yields of total phenolic contents (TPC), total flavonoid contents (TFC) and antioxidants. Under optimal condition, the effective combination of variables was observed in the range of X1: 80 W cm−2, X2: 75%, X3: 0.2, X4: 0.1–0.25 mm and X5: 60 °C. Under this optimum condition, the highest yields of TPC and TFC were found to be 698.4–732.76 mg gallic acid equivalent/g and 67.1–72.67 mg rutin equivalent/g of extract. In addition, their antioxidant activities were found to be 62.5–68.31% 1,1-diphenyl-2-picrylhydrazyl scavenging (DPPHsc), 65.26–69.08% 2,2′-azino-bis (ethylbenzothiazoline-6-sulfonic acid scavenging (ABTSsc) and ferric-reducing antioxidant potential value of 68.5–70.12 μg mol (Fe(II))/g. Experimental and predicted values were found to be identical under this optimum circumstance. Further, biological screening of optimally obtained extract displayed a significant anticancer activity against human adenoma breast cancer cells. © 2019, Iranian Chemical Society.