Recently, there has been more attention on the bioactivity of phytochemicals and other metabolites in agro-food by-products for the management of oxidative stress–related conditions. Hence, the objective of this paper is to assess the nutraceuticals potential by investigating antioxidant and α-amylase inhibitory potentials of seed coat protein isolates from four melon species namely: Citrullus colocynthis, Citrullus mucosospermus, Cucumeropsis mannii and Lagenaria siceraria using appropriate standard methods. At highest concentration, Lagenaria siceraria had the strongest free radical scavenging activity (38% inhibition). The strongest chelating effect was exhibited by C. mannii (IC50 = 0.59 ± 0.08 mg/ml), which also showed highest ferric reducing potential at all concentrations. At 0.05 mg/ml, C. colocynthis, C. mucosospermus, C. mannii, and L. siceraria seed coat protein extracts inhibited alpha-amylase activity by 43.2%, 16.76%, 2.6% and 22.3%, respectively, and inhibition of 60.9%, 28.6%, 38.3% and 29.5% were recorded for the seed protein extracts respectively, at 0.5 mg/ml. In conclusion, the various melon seed coat protein isolates showed appreciable levels of antioxidants and possessed inhibitory activity against α-amylase. Hence, the seed coats of the four melon varieties assessed in this study are promising potential sources of antioxidants for the supplementary treatment of oxidative stress–induced conditions.