DC microgrids have advantages over AC microgrids in terms of system efficiency, cost, and system size. However, a well-designed overcurrent protection approach for DC microgrids remains a challenge. Recognizing this, this paper presents a novel differential evolution (DE) based protection framework for DC microgrids. First, a simplified DC microgrid model is adopted to provide the analytical basis of the DE algorithm. The simplified model does not sacrifice performance criterion in steady-state simulation, which is verified through extensive simulation studies. A DE-based novel overcurrent protection scheme is then proposed to protect the DC microgrid. This DE method provides an innovative way to calculate the maximum line current, which can be used for the overcurrent protection threshold setting and the relay coordination time setting. The detailed load condition and solar irradiance for each bus can be obtained by proposed DE-based method. Finally, extensive case studies involving faults at different locations are performed to validate the proposed strategy’s effectiveness. The expandability of the proposed DE-based overcurrent protection framework has been confirmed by further case studies in seven bus mesh systems.