This paper reports an experimental and numerical study on the spherical indentation behavior of three-dimensional (3D) warp-knitted mesh fabrics. A full-size finite element (FE) model of a typical 3D mesh fabric is established at the yarn level based on the realistic monofilament architecture from micro-computed tomography (μCT) scanning and verified with experiments. The structural change of the fabric in the spherical indentation process is quantitatively analyzed in terms of fabric global deformation, local deformation, mesh deformation, and spacer monofilament deformation from the FE simulation. The numerical results show that the fabric shrinks walewise and expands coursewise from the spherical indentation of the continuous intermeshed monofilament architecture, showing counterintuitive partial auxeticity. The coursewise symmetry and walewise asymmetry of the 3D mesh fabric produce relatively symmetrical coursewise deformation and asymmetrical walewise deformation under spherical indentation. The symmetrical coursewise deformation includes even widening, good fitting of the indenter, and almost identical mesh sizes in the coursewise direction. Walewise asymmetry leads to uneven shortening, inferior fitting of the indenter, and considerably varied mesh sizes in the walewise direction. Spacer monofilaments in different positions relative to the spherical indenter have different deformations. The closer to the indenter, the greater bending and twisting of the spacer monofilament. The spacer monofilament knitted earlier of the tested fabric has smaller deformation than that knitted later due to the walewise asymmetry. The coursewise symmetry and walewise asymmetry of the inhomogeneous 3D mesh fabric structure result in a highly nonlinear spherical indentation behavior.