We report theoretical and experimental investigations of flow through compliant microchannels in which one of the walls is a thin PDMS membrane. A theoretical model is derived that provides an insight into the physics of the coupled fluid–structure interaction. For a fixed channel size, flow rate and fluid viscosity, a compliance parameter $$f_{\text{p}}$$fp is identified, which controls the pressure–flow characteristics. The pressure and deflection profiles and pressure–flow characteristics of the compliant microchannels are predicted using the model and compared with experimental data, which show good agreement. The pressure–flow characteristics of the compliant microchannel are compared with that obtained for an identical conventional (rigid) microchannel. For a fixed channel size and flow rate, the effect of fluid viscosity and compliance parameter $$f_{\text{p}}$$fp on the pressure drop is predicted using the theoretical model, which successfully confront experimental data. The pressure–flow characteristics of a non-Newtonian fluid (0.1 % polyethylene oxide solution) through the compliant and conventional (rigid) microchannels are experimentally measured and compared. The results reveal that for a given change in the flow rate, the corresponding modification in the viscosity due to the shear thinning effect determines the change in the pressure drop in such microchannels. © 2016, Springer-Verlag Berlin Heidelberg.