This study assessed the main determinants of financial performance of the Deposit Money Banks (DMBs) in Nigeria. This study considered bank specific variables, macroeconomic variables in addition to some other control variables over the period from 2009 to 2021. The study employs Fixed Effects Model and Random Effects Model for panel data regression analysis. In examining these, the study explored multiple regression analysis. This paper concludes that bank-specific factors, such as credit risk, liquidity risk, management quality, capital adequacy ratio, asset utilization, firm size leverage and Firm age revealed significant effect on financial performance, while GDP and inflation as macroeconomic factors play a significant role in determining the financial performance of the DMBs in Nigeria. Driven by need to avoid bank instability and failure, the regulatory authorities should pay close attention to the compliance of banks to relevant provisions of the Central Bank of Nigeria (Establishment) Act 2007, Bank and other Financial Institutions Act 2020 (BOFIA) and other provisions in enhancing the efficiency, performance and resilience of banks in Nigeria.