The study investigated the effect of monetary policy instruments on the profitability of deposit money banks in Nigeria, focusing on money supply (M2), exchange rate (EXCH), and interest rate (IR) from 2010 to 2024. Using secondary data from the CBN Statistical Bulletin and employing multiple regression analysis, the study found that money supply (MSPLY) had a significant negative effect on return on assets (ROA) (β = -1.4338; p0.10). Despite some individual effects, the study concluded that overall, monetary policy variables do not significantly influence the profitability of listed deposit money banks in Nigeria. It recommends a cautious and balanced approach in applying monetary policy, particularly money supply, to avoid adverse effects on bank profitability.