Depression is a serious neuropsychiatric disorder associated with disturbances in monoaminergic neurotransmission, oxidative stress, neuroinflammation, and impaired neuroplasticity. Reserpine-induced depression is a widely accepted experimental model that mimics monoamine depletion and depressive-like behavior in animals. Withania somnifera (Ashwagandha) is an important medicinal plant known for its adaptogenic, antioxidant, and neuroprotective properties. The present study aims to evaluate the antidepressant potential of a standardized withanolide-rich extract of Withania somnifera in a reserpine-induced depression model. Piper longum, or long pepper, also exhibited antidepressant properties that were mainly achieved by the mechanism of modulation, especially of serotonin and dopamine. The findings may provide scientific evidence supporting the use of Withania somnifera as a natural therapeutic agent for depression.