Improving the efficiency and sustainability of distribution networks (DNs) is nowadays a challenging objective both for large networks and microgrids connected to the main grid. In this context, a crucial role is played by the so-called network reconfiguration problem, which aims at determining the optimal DN topology. This process is enabled by properly changing the close/open status of all available branch switches to form an admissible graph connecting network buses. The reconfiguration problem is typically modeled as an NP-hard combinatorial problem with a complex search space due to current and voltage constraints. Even though several metaheuristic algorithms have been used to obtain—without guarantees—the global optimal solution, searching for near-optimal solutions in reasonable time is still a research challenge for the DN reconfiguration problem. Facing this issue, this article proposes a novel effective optimization framework for the reconfiguration problem of modern DNs. The objective of reconfiguration is minimizing the overall power losses while ensuring an enhanced DN voltage profile. A multiple-step resolution procedure is then presented, where the recent Harris hawks optimization (HHO) algorithm constitutes the core part. This optimizer is here intelligently accompanied by appropriate preprocessing (i.e., search space preparation and initial feasible population generation) and postprocessing (i.e., solution refinement) phases aimed at improving the search for near-optimal configurations. The effectiveness of the method is validated through numerical experiments on the IEEE 33-bus, the IEEE 85-bus systems, and an artificial 295-bus system under distributed generation and load variation. Finally, the performance of the proposed HHO-based approach is compared with two related metaheuristic techniques, namely the particle swarm optimization algorithm and the Cuckoo search algorithm. The results show that HHO outperforms the other two optimizers in terms of minimized power losses, enhanced voltage profile, and running time. Note to Practitioners—This article is motivated by the emerging need for effective network reconfiguration approaches in modern power distribution systems, including microgrids. The proposed metaheuristic optimization strategy allows the decision maker (i.e., the distribution system operator) to determine in reasonable time the optimal network topology, minimizing the overall power losses and considering the system operational requirements. The proposed optimization framework is generic and flexible, as it can be applied to different architectures both of large distribution networks (DNs) and microgrids, considering various types of system objectives and technical constraints. The presented strategy can be implemented in any decision support system or engineering software for power grids, providing decision makers with an effective information and communication technology tool for the optimal planning of the energy efficiency and environmental sustainability of DNs.