Sporisorium reilianum (S. reiliana) is rich in nutrition, high in melanin content, and can be obtained by artificial species. It is a high-quality raw material for extracting natural melanin. Because of its unique structure and physicochemical property, natural melanin has become a stable and unique rare species in natural pigments. In this study, the effect of ultrasonic assisted on melanin extraction was studied with S. reiliana as a material. The influences of ultrasonic power, temperature, time, NaOH extract on melanin extraction in S. reiliana were investigated respectively. And through the single factor test and response surface method (RSM) to verify the evaluation. The RSM optimum conditions for melanin accumulation were: Ultrasonic power 245W, temperature 50°C, time 2 h, and pH 13 of NaOH extract. Under this condition, the return is 3.52%, which is close to the predicted value, indicating the feasibility of this model. For α-glycosidase and PTP1B inhibition assay, the melanin demonstrated the inhibitory effect with IC50 82.16 ± 5.02 μg/ml and 81.27 ± 10.48 μg/ml, respectively. This study reveals the hypoglycemic activities of the melanin isolated from S. reiliana for the first time. Practical applications Melanin from S. reiliana is an excellent hypoglycemic product due to its high α-glycosidase and PTP1B inhibition activity. However, its extraction yield is too low. The combination of unconventional techniques (ultrasound-assisted alkali dissolution and acid precipitation) is characterized as a new methodology for the extraction of melanin from S. reiliana. The extract provided a higher content of melanin than conventional methods. This technique is easily incorporated at the industrial level and is the low cost after the purchase of the relevant equipment.