The banking sector is one of the most important sectors in South Africa. There are various determinants that influence the profitability of the banking sector. This study investigated the determinants of bank profitability in South Africa. Understanding these determinants may benefit investors, managers, and regulators and can contribute to a stable banking sector. The study employed panel data of the five biggest banks in South Africa from 2006 to 2023. Fixed-effects panel regression models were applied to assess the impact of bank-specific (asset quality, operational efficiency, capitalisation, and liquidity) and macroeconomic factors (inflation, GDP growth, exchange rates, and interest rates) on bank profitability. Return on assets was used to measure profitability. A negative relationship between profit and the liquidity ratio was identified, which indicates that profitability is lowered by excess liquidity. A positive relationship between profit and asset quality, capitalisation, GDP, and lending interest rates was identified. This suggests that high-quality assets, robust economic growth, well-capitalised banks, and higher lending rates contribute to increased profitability. Understanding this impact can aid investors, managers, and regulators in the banking sector. A limitation of the study is that the five largest banks in South Africa were investigated, which excluded smaller banks and other financial institutions.