© 2019 IOP Publishing Ltd. The fluid flow and mixing characteristics of planar serpentine microchannels consisting of repeating S-shaped units was characterized both computationally and experimentally for Reynolds numbers Re < 100. In particular, it was found that using non-rectangular cross-sections with changing orientation for the geometrical units greatly enhances their mixing performance relative to standard rectangular profile serpentine channels. The optimization of the cross-section enables efficient mixing of two-fluid components at Reynolds numbers as low as 20, making these designs practical for chemical reaction engineering and biological assays platforms. A computational analysis of the cross-sectional flow structures present in this type of channels indicates that their enhanced performance is correlated with the formation of secondary transversal vortexes. In the optimal designs, their presence increases the mass transfer in the microchannel by both stretching the interface between the fluid components to be mixed, as well as by promoting chaotic advection.