This paper reports the design and numerical analysis of a three‐dimensional biochip plasma blood separator using computational fluid dynamics techniques. Based on the initial configuration of a two‐dimensional (2D) separator, five three‐dimensional (3D) microchannel biochip designs are categorically developed through axial and plenary symmetrical expansions. These include the geometric variations of three types of the branch side channels (circular, rectangular, disc) and two types of the main channel (solid and concentric). Ignoring the initial transient behaviour and assuming that steady‐state flow has been established, the behaviour of the blood fluid in the devices is algebraically analysed and numerically modelled. The roles of the relevant microchannel mechanisms, i.e. bifurcation, constriction and bending channel, on promoting the separation process are analysed based on modelling results. The differences among the different 3D implementations are compared and discussed. The advantages of 3D over 2D separator in increasing separation volume and effectively depleting cell‐free layer fluid from the whole cross section circumference are addressed and illustrated. Copyright © 2011 John Wiley & Sons, Ltd.