This study examines the determinants of bank profitability in Indonesia from 2012 to 2023, using quarterly data from 50 banks listed on the Indonesia Stock Exchange. Return on Assets (ROA) and Return on Equity (ROE) are employed as profitability measures, while capital adequacy ratios measured by total capital to total assets and total capital to risk weighted assets, equity ratios, cost-to-income ratios, debt-to-equity ratios, bank size, and non-performing loans are investigated as explanatory variables. Results from panel regression analysis reveal that both capital adequacy ratios, equity ratios, debt-to-equity ratios do not significantly impact profitability. In contrast, cost-to-income ratios, bank size, and non-performing loans negatively impact both ROA and ROE, underscoring the importance of operational efficiency and credit risk management in enhancing profitability. The analysis is further refined using machine learning techniques, specifically Random Forest and XGBoost, which confirm that cost-to-income ratios, non-performing loans, and bank size are the primary factors affecting bank profitability. These findings provide practical insights for bank management, policymakers, and regulators in developing strategies to enhance bank profitability.