Background: Profitability is the primary measure of the overall success of company. The analysis of profitability ratios is important for the shareholders, creditors, prospective investors, manufacturers and government alike. Objective: The objective of this study was fitted a dynamic panel regression model that efficiently fit the data and further to identify the determinants contributing significantly to profitability in Ethiopia. Methods: This study was conducted on secondary data of 32 sample manufacturing companies collected from the audited financial statements of large tax payers’ office and national bank of Ethiopia. The study was covered a period of seven years from 2011 to 2017. The panel unit root test of Levin-Lin-Chu tests was made for each variable and applied first difference transformation for the variables that had unit root. A dynamic panel regression model was utilized for data handling technique using generalized method of moments (GMM) estimation. Results: We compared the results when one unit increase in lagged profitability, managerial efficiency, capital intensity, GDP, exchange rate and one ratio decrease in leverage, ceteris paribus, turn out were found to increase the profitability of manufacturing companies by around 0.69, 0.179, 4.52E-06, 3.844, 0.04 and 0.393 ratio, respectively. The model reveled that previous profitability, leverage, capital intensity, managerial efficiency, GDP and exchange rate had a statistically significant (P<0.05) effect on companies’ profitability in Ethiopia. Conclusion: As per our findings, the manufacturing companies should minimize leverage financing from its capitals and should emphasize the management of appropriate financing to increase profitability. Finally, we recommended that policy makers should coming up with better policies on improvement of profitability.