This research paper aims to investigate the impact of different components of Du-Pont model on firms' profitability (1) on stand-alone basis, and (2) in the presence of different macroeconomic factors. These components include profit margin, total assets turnover and financial leverage. Financial information from five different sectors of Pakistan's economy comprising of automobile, cement, fertilizer, oil and gas and power & distribution was collected for years ranging from FY2011 to FY2017. Few macroeconomic factors such as Exchange Rates, GDP, Inflation, and Interest rates are also taken into consideration. In this paper, LS and GMM regression models have been implied on Du-Pont model (financial ratios) and the results indicate that profit margin is a major driver of profitability amongst all the other factors of Du-Pont across various economic sectors of economy of Pakistan. Hence, the business managers should exert more focus on adjusting the micro-economic factors, perhaps profitability, while adapting to macroeconomic factors