Micro-particle manipulation, based solely on the Dean drag force, has begun to be advocated for with the goal of lowering the pumping pressure and simplifying the complexity of the coupling effects of the inertial lift force and the Dean drag force, thus reducing the difficulty of theoretically predicting particle motion. We employed the CFD-DEM two-way coupling method in this work to quantitatively study the lateral (z in axis) motion of particles (7−10 μm), in square or half-circle segment serpentine microchannels, that was only reliant on Dean drag with the blockage ratio dDh= 0.04 (the inertial lift effects show at dDh>0.07). In the square-segment serpentine channel, under the conditions of single-side-wall sheath flow and sedimentation, we discovered that the particles exhibit a twist-type lateral trajectory around each turn, with the larger particles always twisting in the opposite direction of the smaller particles, as a result of the four-grid-pattern distribution of the lateral velocity values at each turn. The large and small particles are separated at the channel’s exit at Re = 56.7, De = 17.8, indicating the likelihood of separation only due to the Dean drag. This separation efficiency decreases as Re and De decreases. The lateral position and velocity values of the particles oscillate, as time passes, due to the twist trajectory, with the oscillation amplitude increasing as Re or De decreases and deflecting toward the inner side of z. In the cases of the two-side-wall-symmetric sheath flow, the particles exhibit only a little lateral deflection, and particle separation is not achieved. The deflection of the oscillation is uncertain and does not change regularly with any physical quantity.