Understanding the complex interaction between deep foundations and layered soil profiles is critical for the seismic design of high-rise structures. This study conducts a nonlinear dynamic soil pile structure interaction (DSPSI) analysis of a 20-storey reinforced concrete building supported by layered sandy soil, emphasizing the influence of nonlinear soil pile interface behaviour. A detailed three-dimensional finite element model is developed, incorporating three structural configurations: a regular frame and two vertically irregular frames featuring upper-storey geometric discontinuities. The stratified sand deposit is modelled with depth-varying stiffness, and horizontal damping layers are embedded to capture energy dissipation mechanisms. Two pile configurations, series and 2 × 2 grouped arrangements, are examined across two length-to-diameter (L/D) ratios, maintaining a consistent pile spacing of 3D. The study evaluates key seismic response parameters, including lateral deformation, storey drift, base shear, lateral pile displacement, and settlement. The results demonstrate that nonlinear interface modelling significantly alters seismic response trends and enhances the accuracy of performance predictions. These findings underscore the importance of advanced nonlinear interface modelling and optimized pile configurations in improving the seismic resilience of high-rise buildings founded on sandy soil.