This study examined the paradox of natural resource abundance and chronic underdevelopment in Africa — a phenomenon widely theorised as the "resource curse" — through a rigorous political economic lens spanning 20 African countries over the period 2000 to 2022. Despite holding approximately 30% of the world's mineral reserves and a substantial share of global hydrocarbon deposits, most resource-rich African nations continued to register lower human development indices, weaker governance scores, greater income inequality, and slower rates of structural economic transformation relative to their resource-poor counterparts on the continent. The study was anchored on three core objectives: to assess the statistical relationship between natural resource dependence and key development outcomes; to evaluate the moderating role of governance quality on this relationship; and to model the projected developmental impact of alternative structural transformation scenarios. Employing a mixed-methods analytical strategy, the study generated panel data for 20 countries across 23 years, yielding 1,380 country-year observations. Univariate descriptive statistics established the baseline distributional characteristics of key variables including GDP per capita, the Human Development Index (HDI), resource rents as a proportion of GDP, World Bank Governance Indicators (WGI), GINI coefficients, and manufacturing sector output. Bivariate Pearson correlation analyses revealed statistically significant negative associations between resource rent dependency and both HDI (r = −0.489, p < 0.001) and governance quality (r = −0.612, p < 0.001), while manufacturing output showed a strong positive correlation with GDP per capita (r = 0.716, p < 0.001). Three-level random effects regression models — incorporating country-level and year-level fixed effects alongside cross-level interaction terms — confirmed that resource rent dependency exerted a significant negative effect on the composite development index (β = −0.176, p < 0.001) even after controlling for income levels, governance, inequality, and foreign direct investment. Critically, the interaction of resource rents with governance quality (β = −0.158, p < 0.001) demonstrated that poor institutional environments substantially amplified the curse effect, while manufacturing sector expansion significantly buffered against it. Policy simulation scenarios further projected that a combined strategy of governance reform, manufacturing expansion, and reduced resource rent dependency could yield a 16.4% improvement in composite development outcomes, rising to 25.4% under a full structural transformation scenario. These findings reinforced the theoretical propositions of the Dutch Disease model, the rentier state hypothesis, and heterodox structuralist development theory. The study concluded that Africa's resource curse was neither inevitable nor permanent, but was fundamentally a governance and structural transformation failure that demanded decisive, state-led industrial policy, institutional reform, and regional economic integration as the imperative pathway forward.