This study analyzes the macroeconomic and institutional factors influencing debt sustainability in Ghana, focusing specifically on the debt service-to-export ratio (DSEX) as the dependent variable. This study incorporates essential macroeconomic indicators, including Gross Domestic Product (GDP) growth, inflation rate, interest rate, public debt, and export performance, while considering institutional quality as a moderating variable. Annual time-series data from 1990 to 2022 were obtained from the World Bank and International Monetary Fund (IMF) databases. The analysis utilised Ordinary Least Squares (OLS) regression and interaction modelling techniques to examine direct and moderating effects. The findings indicate that GDP growth, inflation, and export performance do not significantly impact the DSEX. However, interest rates and public debt have statistically significant positive effects, implying that increasing borrowing costs and elevated debt levels exacerbate Ghanaian’s external debt burden. Contrary to theoretical expectations, institutional quality does not moderate the relationship between public debt and DSEX, suggesting a limited institutional influence on transforming growth into sustainable debt outcomes. The findings are consistent with the Solvency Constraint Theory and the Debt Overhang Hypothesis, yet they reveal limitations in the predictive capacity of Institutional Theory in this context. The originality of this study is rooted in its integrated approach that combines macroeconomic and institutional variables within a singular empirical framework tailored to Ghana. Policy recommendations include improving fiscal discipline, decreasing reliance on non-concessional debt, and bolstering institutional capacity. Future research should utilise dynamic modelling and comparative analysis among similar economies to validate these relationships and reveal context-specific insights.