In this article, a systematic design approach is presented to reduce the mutual coupling between a pair of closely spaced microstrip patch antennas (MPAs). This method can effectively overcome the main drawback of previous two-path cancellation methods, i.e., lack a systematic design guideline and heavily rely on the time-expensive trial-and-error procedure to mitigate mutual coupling in a best-effort manner. To this end, we first propose the concept and workflow of the systematic design method, and introduce the circuit-level modeling upon the proposed two coupling routes. Then, prototyped on a practical and simple physical structure, we perform certain accurate extractions and derive the rigorous conditions for both of isolation between two patches and impedance matching of a single patch based on these two paths. Afterwards, according to the circuit-level discussion on lumped elements, the corresponding decoupling structure could be implemented substantially and designed quantitatively at the antenna level for particularized closely spaced MPAs. Finally, a prototype is simulated, fabricated, and measured to validate the proposed method. The results show that the circuit-model calculation, full-wave simulation, and measurement are in good agreement. By virtue of such a simple decoupling structure, the poor 7-dB isolation is dramatically improved to 58 dB, and the isolation is enhanced beyond 20 dB in the entire impedance matching bandwidth range of 4.38 4.60 GHz (4.9%), with the closely center-to-center spacing of 0.37λ 0.