In the present work, the mechanical performance of novel sandwich composite panels based on 3D-knitted spacer fabrics has been investigated. Composite panels were produced using three different types of spacer fabrics having different structural parameters. The sandwich panels were fabricated based on an unsaturated polyester resin using a modified vacuum-assisted resin transfer molding process which allowed the formation of low-density core structures. The produced sandwich composite panels were characterized for flexural, compressive, and impact properties. The effect of different fabric structural parameters (such as cross-thread density, linear density of yarn used in face and core, and structure of face) on the processability and mechanical behavior of composite panels has been thoroughly investigated. The results showed that the composite panels based on spacer fabrics having lesser cross-thread density and made of coarser yarns performed better with respect to compressive and impact properties, whereas the best flexural properties were obtained in case of spacer fabrics with high cross-thread density and made of finer yarns.