•CFD-DEM model is applied to predict gas-solid flow dynamics in the full-loop CFB with multiple cyclones.•Pressure drop within middle components are slightly smaller than within other components.•The axial symmetry arrangement for the parallel cyclones is better than the central symmetry arrangement. Multiple cyclones are adopted to enlarge the capacity of circulating fluidized bed (CFB). In this work, the effect of cyclone arrangements on the gas-solid flow dynamics in the three-dimensional full-loop CFB is investigated by the computational fluid dynamics coupled with discrete element method (CFD-DEM). Flow patterns, pressure distribution, and non-uniform distribution of the gas-solid flow in the CFB is comprehensively studied. Results show that the CFB with multiple cyclones gives rise to some unique characteristics, including: (i) solid back-mixing behavior mainly occurs close to the front and back walls and in the four corners of the riser; (ii) the spiral directions of the internal and external vortexes of gas flow in the cyclone are same; (iii) the closed-loop pressure is obtained and the pressure drop in the standpipe and L-valve are nearly four times of that in the cyclone; (iv) gas-solid flow shows non-uniform distribution in the multiple cyclones, and the middle cyclones have higher solid holdup and solid velocity than the corner cyclones; (v) the axial symmetry arrangement for the multiple cyclones is better than the central symmetry arrangement in terms of the uniform distribution of solid flux in the cyclone and solid inventory in the standpipe. The results provide meaningful understanding for the design, scale-up, and optimization of CFB apparatuses.