When the World Health Organization (WHO) declared COVID-19 as a pandemic that will be rapidly spreading around the world, it had significant implications on financial institutions, including Islamic banks, as they faced challenges in maintaining operations and managing risks during this unprecedented crisis. Thus, this study was conducted to analyse the relationship between the independent variables with return on assets and to determine the significant determinants of Islamic banks’ profitability performance during COVID-19. The dataset for this study were derived and collected from annual reports of the ten local Islamic banks in Malaysia for three years (2019-2021). Capital adequacy ratio (CAR), non-performing loan (NPL), operational efficiency (OEF) and bank size (SIZE) are chosen as the independent variables, while return of assets (ROA) as the dependent variable. Using Pearson correlation, it is found that CAR has a weak positive relationship, while NPL, OEF and SIZE have a weak negative relationship with ROA. This study also employs panel regression analysis, using a fixed effects model as the best estimator to determine the significant factors. The findings of the panel data regression analysis shows that only two variables were found to be positively significant, which are CAR and NPL, while OEF and SIZE are found to be insignificant with the profitability performance of Islamic banks.