Aframomum melegueta seeds (AMS) is an African spice with well known traditional and therapeutic values. Its pharmacological activities are attributable mainly to phenolics. This study aimed to investigate and optimize the parameters affecting the ultrasound-assisted extraction (UAE) of AMS major constituents and total phenolic content (TPC) using response surface methodology. 6-gingerol, 6-shogoal and 6-paradol were isolated from AMS and a Box-Behnken design (3 factors /3 levels) was used to determine the effect of three extraction parameters (extraction time, methanol concentration and liquid/solid ratio) on their extraction yield. The results showed that methanol concentration and liquid/solid ratio have positive and significant impact on the UAE of TPC and the three investigated compounds, while extraction time has no significant effect. Under optimal conditions, each 1 g dry sample provides 9.32±0.02 mg, 3.72±0.01 mg, 12.32±0.04 mg and 10.71±0.19 mg/GAE of 6-gingerol, 6-shogoal, 6-paradol and TPC, respectively. The optimized UAE conditions were validated and are recommended for the recovery of 6-gingerol, 6-shogoal, 6-paradol and TPC from AMS for further applications as alternative to conventional extraction method.