This paper aims to investigate the bank-specific characteristics and macroeconomic factors affecting the profitability performance of the Southeast Asian banking sector. The sample markets cover the five original members of ASEAN, i.e. Indonesia, Malaysia, Philippines, Singapore, and Thailand, whereas the sample period encompasses the years between 2010 and 2017. While a healthy financial system is important for the economic sustainability and growth, there are still limited studies to understand how banks generally perform in this region. Our findings largely support the existing hypotheses about the importance of certain micro- and macro variables while contributing new empirical evidence to the current literature. The bank size, loan to assets, loan loss provision, non-interest incomes and expenses, and capital adequacy remain relevant in influencing bank profitability in the ASEAN-5 region. Macroeconomic variables of inflation, interest rate, market concentration and GDP per capita play considerable roles in profitability when they are assessed separately from the bank-specific factors. It is worth noting that the bank-level factors remain important and outplay the macroeconomic factors when they are considered at the same time. The result robustness is of a certain level of satisfaction because comparisons have been performed across individual countries and across different regression models of pooled ordinary least squares model, random effect model, and fixed effect model for all the tentative tests. Both the return on assets and return on equity are examined. Combining both micro- and macroeconomic variables in the regressions also indicates an overall improvement in the r-squared under the same models.