This paper investigated determinants of bank's profitability and accounted for the role of financial crisis in Nigeria using four big commercial banks in Nigeria. The bank specific factors include operating efficiency ratio and liquidity ratio while the macroeconomic factors include lending interest rate, consumer price index and financial crisis. The data for this study was collected from the annual report of these banks over the periods of 2003 to 2014 and CBN Statistical Bulletin and the data were analysed applying Ordinary Least regression (OLS) estimation technique. The result from the panel regression suggested that operating efficiency ratio and inflation rate were negatively related to bank profitability in Nigeria. In addition, the result showed that lending interest rate have significant (p<0.05) impact on profitability of bank and that 2008 financial crisis did not have significant effect on banks' profitability during the study period. The study therefore suggested that operating efficiency ratio, lending interest rate and financial crisis liquidity ratio and inflation rate are major endogenous determinants of bank profitability in Nigeria. It recommends that regulatory authorities should promote policies that will bring about low inflation whereas bank management should concentrate more on reducing expenses