Citrullus colocynthis (C. colocynthis) seed is a common and expensive cuisine in West African diet unlike the seeds from Citrullus lanatus (C. lanatus) that are agro waste. The oils from these seeds were comparatively profiled using their physicochemical properties, fatty acids and phenolic contents, in-vitro antioxidant capacity (DPPH, TEAC, FRAP, ORAC), inhibitions of lipid peroxidation and tyrosinase. Toxicities of the oils in mice were also assessed using plasma AST, ALT, cholesterol, HDL-C, liver, heart and kidney (GSH, GPx and SOD) and clastogenic effects in mouse bone marrow. Citrullus lanatus oil contains higher peroxides, saponification, saturated fatty acids and stearic acid (6-fold) levels, with a lower acid value when compared to C. colocynthis. Strong antioxidant capacity, inhibition of lipid peroxidation and tyrosinase by C. lanatus oil extract is proposed to be related to the presence of catechins that are absent in C. colocynthis. The in-vivo study indicated that C. lanatus induced significant increase in ALT while a significant increase of AST was observed in the C. colocynthis treated group. Citrullus lanatus induced a significantly (p<0.05) higher heart GPx activity when compared with C. colocynthis and the control groups. Both oils did not affect SOD activity and showed no clastogenic effect in mouse bone marrow (p>0.05). This work reports for the first time the presence of stearic acid and catechin in C. lanatus oil which is important for its compelling in vitro activity. High doses of both oils could evidently induce toxicological indices in mice.