A uniform arrangement of individual piles is commonly adopted in the conventional pile group foundation, and basin-shaped settlement is often observed in practice. Large differential settlement of pile groups will decrease the use-safety requirements of building, even cause the whole-building tilt or collapse. To reduce differential settlement among individual piles, non-uniformly arranged pile groups can be adopted. This paper presents a finite element analysis on the response of pile groups with different layouts of individual piles in pile groups. Using the user-defined subroutine FRIC as the secondary development platform, a softening model of skin friction and a hyperbolic model of end resistance are introduced into the contact pair calculation of ABAQUS software. As to the response analysis of a single pile, the reliability of the proposed secondary development method of ABAQUS software is verified using an iterative computer program. The reinforcing effects of individual piles is then analyzed using the present finite element analysis. Furthermore, the response of non-uniformly arranged pile groups, e.g., individual piles with variable length and individual piles with variable diameter, is analyzed using the proposed numerical analysis method. Some suggestions on the layout of individual piles are proposed to reduce differential settlement and make full use of the bearing capacity of individual piles in pile groups for practical purposes.