The objective of this study is to design spacers using topology optimization in a two-dimensional (2D) crossflow reverse osmosis (RO) membrane channel in order to improve the performance of RO processes. This study is the first attempt to apply topology optimization to designing spacers in a RO membrane channel. The performance was evaluated based on the quantity of permeate flux penetrating both the upper and lower membrane surfaces. Here, Navier–Stokes and convection-diffusion equations were employed to calculate the permeate flux. The nine reference models, consisting of combinations of circle, rectangle, and triangle shapes and zig-zag, cavity, and submerged spacer configurations were then simulated using finite element method so that the performance of the model designed by topology optimization could be compared to the reference models. As a result of topology optimization with the allowable pressure drop changes in the channel, characteristics required of the spacer design were determined. The spacer design based on topology optimization was then simplified to consider manufacturability and performance. When the simplified design was compared to the reference models, the new design displayed a better performance in terms of permeate flux and wall concentration at the membrane surface.