There is a strong association between depression and memory impairment. The present study aims to assess the nootropic activity ofduloxetine and piracetam combination. Male Swiss Albino mice were divided randomly into 4 groups. Treatment of normal saline(10 ml/kg), duloxetine (10 mg/kg), piracetam (100 mg/kg), and duloxetine (5 mg/kg) plus piracetam (50 mg/kg) were given throughintra-peritoneal route to group I-IV, respectively. Transfer latency in elevated plus maze (EPM) and time spent in target quadrant inMorris water maze (MWM) were recorded. Estimation of brain monoamines in hippocampus, cerebral cortex, and whole brain weredone using HPLC with fluorescence detector. Piracetam treated group showed significant decrease in transfer latency in EPM andincrease in time spent in target quadrant recorded in MWM. Combination treated group failed to produce statistically significantnootropic effect in both EPM and MWM. Combination treated group failed to increase brain monoamine levels when comparedagainst duloxetine and piracetam treated groups, separately. But there was exception of significant increase in norepinephrinelevels in hippocampi when compared against duloxetine treated group. Results indicate no cognitive benefits with piracetam plusduloxetine combination. These findings can be further probed with the aim of understanding the interaction between duloxetineand piracetam as a future endeavor.