The financial system of Vietnam’s economy considers the banking system as the engine for its development and the growth of economy just like other countries in the world. Similar to most other private sectors, in order to sustain and develop the business, commercial banks need to earn and maintain positive and growing profitability. However, in the volatile business environment and during the economic transitional stage, banking sector tends to suffer unstable profitability and declining performance. Therefore, this research is carried out with the purpose to investigate which factors are the key determinants or driver of the profitability of commercial banks in Vietnam in the past 10 years. By reviewing prior studies and evidence from different countries and regions in the world, this research is going to supplement the current studies in Vietnam with a more potential factors that can potentially drive the profitability of local banking sectors. Internal factors such as financing structure, assets structure, asset quality, capitalization, operating efficiency, size of bank and income diversification will be studied in relation with profitability. Besides internal factors, external or macro-economic factors such as GDP growth rate, inflation rate and market concentration are also taken in to evaluation. This research contributes to existing literature by introducing the role diversification, non- performing loans, operating efficiency and banking sector concentration level in the context of Vietnam. Multiple linear regression for balance panel data will be employed to serve the purpose of this research. Data includes 16 largest banks in Vietnam during the period of 10 years from 2007 to 2016. The outcomes are relatively mixed. While it suggests the significant effect of market concentration level, the importance of capitalization, the ability to manage the banks effectively and control non-performing loans, there is not enough evidence to support the benefit of income diversification. Besides, the loans level and bank size are found to be not relevant in the context of Vietnam.