Non-uniform cross-sectional designs of serpentine channel in direct methanol fuel cells are systematically studied in the present work. A parametric design is proposed to describe and classify channel geometries whose effects on cell performance are numerically and experimentally analyzed. Numerical results show that the non-uniform converging designs are beneficial for both in- and through-plane methanol transportations, and thus to enhance the peak power generation performance as much as 12% at high-current-density operations. Effectiveness of non-uniform designs for power generation enhancements is also validated by experimental studies which consider various operating conditions, and significant enhancement of power generation (18.4%) is noticed by the usage of non-uniform converging design. Optimal application conditions for the non-uniform converging designs are determined to be the high-current-density operations with high temperatures.