Background: Depression is one of the most common types of neurological disorder, which is a marked pattern of disturbances in emotional behavior, memory and hedonic processing. Aim and Objectives: To investigate the role of ethanolic extract of Theobroma cacao seed on the prefrontal cortex of female Wistar rats following reserpine-induced depression. Material and Methods: Thirty-six (36) female Wistar rats were used for this study. They were divided into six (A - F) groups (n = 6). Group A- control, Group B - 0.2 mg/kg reserpine, Group C - 10 mg/kg fluoxetine, Group D - 500 mg/kg Theobroma cacao seed extract, Group E - 0.2 mg/kg reserpine + 500mg/kg Theobroma cacao seed extract, Group F - 0.2 mg/kg reserpine + 10mg/kg fluoxetine. Animals were euthanized via cervical dislocation after the last day of administration and the prefrontal cortex and hippocampus were excised and fixed in 10% formalin solution for routine histological processing while the part used for biochemical assay were homogenized in phosphate buffer before centrifugation. Results: Morphological alteration and reduced population of prefrontal cortex and hippocampus neurons, reduced protein synthesis, poor behavioral patterns, reduced neurotransmission and induction of oxidative stress in reserpine exposed animal. Conclusion: Theobroma cacao seed extract was able to mitigate these aberrations.