Physicochemical characterization (i.e., solubility, stability, UV–vis, IR, ¹H and ¹³C NMR, and thermogravimetric and elemental analysis) and biological activities (antioxidant and immunomodulatory) of purified melanins from the fruit flesh of Vitex mollis (VM) and Randia echinocarpa (RE) were investigated. The melanins showed low solubility, light stability, oxidation by chemicals, metal chelation, degradation temperature at 350 °C, % nitrogen (VM 3.725 and RE 4.485), characteristic spectroscopic signals, high antioxidant activity (µmol TE/g) (ABTS, VM 1333.5 and RE 835.7; FRAP, VM 1098.41 and RE 709.64), protective effect against H₂O₂-stress in Saccharomyces, and an induction of splenocyte proliferation. The chemical and biological data support that melanins of VM and RE are biosynthesized from tyrosine and have potential as photoprotective agents and could be considered for the prevention/treatment of chronic degenerative diseases. The fruits of VM and RE could be used to develop high added-value products favoring their preservation and sustainable exploitation.