Nowadays, the high penetration of automation on smart grids challenges electricity companies in providing an efficient distribution networks operation. In this sense, distribution system reconfiguration (DSR) plays an important role since it may help solve real-time problems. This paper proposes a methodology to solve the DSR problem using artificial immune systems (AIS) based on a new, efficient, and robust approach. This new methodology, called Enhanced Artificial Immune Systems (EAIS), uses the values of the currents in wires for intelligent mutations. The problem is accomplished by a multi-objective optimization with fuzzy variables, minimizing power losses, voltage deviation, and feeders load balancing. A comparison with other DSR solution methods is presented. The method is compared with two other previously proposed methods with the help of the 33-bus, 84-bus, and 136-bus distribution systems. Different scenarios are analyzed, including the optimal location of the Distributed Generation (DG). The results show the applicability of the proposed algorithm for the simultaneous solution of DSR and location or dispatch of DGs.