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This study aimed the optimization of antioxidant activity, total phenolic compounds (TPC) and total carotenoids of Horned Melon fruit submitted to maceration extraction, using ethanol as solvent. Optimization was performed by Box–Behnken design on three levels and three variables: extraction temperature (25 °C, 55 °C, and 85 °C), extraction time (0.5, 2.0, and 3.5 h) and ethanol concentration (10%, 50%, and 90%). The optimal conditions to improve the carotenoids extraction was 55 °C, 1.5 h and 86% ethanol, whereas the antiradical/antioxidant activity (ABTS and FRAP assays) and TPC were enhanced at 45 °C for 2.0 h and 40% ethanol. The optimal antioxidant extract was characterized regarding the phenolic composition and in vitro neuroprotective activities. The phenolic composition revealed the presence of high amounts of gallic acid (11.7 ± 0.6 mg/100 g dw) and protocatechuic acid (7.69 ± 0.38 mg/100 g dw). However, this extract presented a weak activity against Monoamine oxidase A (11.8 ± 2.3% inhibition at 2.7 mg/mL) and did not display anti-cholinesterase activity at the maximum concentration tested (1.3 mg/mL). Maceration was an efficient extraction technique to recover polyphenols and carotenoids from Horned Melon fruit. The optimized model can be very useful for food and pharmaceutical industries. [ABSTRACT FROM AUTHOR]