In the present work, the ultrasonic-assisted extraction (UAE) of total flavonoids (TF) from Pteris cretica L. was optimized by response surface methodology (RSM) on the basis of a single-factor experiment. The optimized UAE parameters were as follows: Ethanol concentration 56.74%, extraction time 45.94 min, extraction temperature 74.27 °C, and liquid/solid ratio 33.69 mL/g. Under the optimized conditions, the total flavonoids yield (TFY) was 4.71 ± 0.04%, which was higher than that obtained by heat reflux extraction (HRE). The extracts were further analyzed by HPLC, and five major flavonoids, including rutin, quercitrin, luteolin, apigenin, and luteolin-7-O-glucoside, were identified and quantified. Furthermore, the results of the antioxidant test showed that the TF extract obtained under optimized UAE conditions exhibited good 2,2-diphenyl-1-picrylhydrazyl radical (DPPH•) and 2,2-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radical (ABTS+•), nitric oxide radical (NO•) scavenging activities, and ferrous ion (Fe2+) chelating capacity, with IC50 values of 74.49, 82.92, 89.12, and 713.41 µg/mL, respectively. Results indicated that the UAE technique developed in this work was an efficient, rapid, and simple approach for the extraction of flavonoids with antioxidant activity from P. cretica.