The main objective of this paper is to explore the most significant determinants of financial distress of manufacturing companies in Indonesia and to provide explanations on this issue by using multiple regression models. With Modigliani and Miller’s and Trade-off theories were reviewed to formulate a testable proposition on the determinants of financial distress of manufacturing companies in Indonesia. Multiple regression models were used as a statistical tool to investigate the most significant profitability determinants of manufacturing companies in Indonesia. The Lisrel software was used to analyze 300 manufacturing companies listed on the Indonesia Stock Exchange. It was found that institutional ownership, firm size, profitability, and board independence as variables had a positive relationship in an effort to avoid financial distress. Meanwhile, the board size variable had an insignificant positive relationship. The findings are consistent with the pecking order and financial agency theory which helps in understanding the application of financial distress studies for manufacturing companies in Indonesia.