This study empirically investigated the relationship between resource depletion and economic growth in Nigeria. The specific objectives of the paper were to evaluate the impact of resource drivers on natural resource depletion as well as the impact of resource depletion and environmental pollution on economic growth. The study employed time series data from 1990 to 2022 on real gross domestic product (RGDP), population growth (POP), total natural resource depletion (R_DEP) and energy depletion (E_DEP) - proxied as the percentage of gross national income – while CO2 emission and human capital index (HDI) served to proxy environmental pollution and human capital development, respectively. Moreover, the paper utilised the ARDL and the Johansen Cointegration approach in the estimation of the specified models. The findings of the study show that economic activities and population growth significantly devalue natural resources in the short run, while human capital index has a countervailing influence on natural resource depletion. In addition, the findings revealed evidence of the existence of long-run relationship between energy depletion, CO2 emission, HDI and economic growth, as well as unidirection causality from energy depletion to human capital development. The paper therefore recommended the strategic development of human resource capital as it is a vital ingredient for evolving alternatives to resource dependence.