Hybrid lattice configurations that incorporate diverse structural units offer a promising pathway to tailor the mechanical performance of hybrid lattice sandwich structures. A deeper understanding of the underlying mechanisms governing how hybridization influences global structural responses is essential for establishing rational design strategies. In response to the requirements of mechanical performance regulation in hybrid structures, this study investigates the influence mechanisms of core-layer unit hybridization on the mechanical performance and deformation characteristics. Based on the specific modulus and yield stress responses of eight representative lattice structure units, four units with significant geometric and mechanical disparities were strategically selected, and ten substitution-type hybrid core configurations were developed through spatial arrangement optimization. The corresponding lattice sandwich structure specimens were fabricated via fused deposition modeling (FDM). Combined with finite element analysis and compressive experiments, the effects of substitution configuration on load-bearing characteristics and deformation modes were revealed. The results demonstrate that the performance difference between the substitution units and the matrix units dominates the deformation mode transition in hybrid structures. Weak-unit substitution in strong matrices induces premature core-layer activation, reducing overall specific modulus and yield stress of the structure by 41.78% and 25.58%, and 45.19% and 26.07%, respectively, compared to their homogeneous counterparts with all hybrid combinations exhibiting similar mechanical performance at equivalent substitution volume fractions. Conversely, strong-unit substitution in weak matrices delays core densification while enhancing load redistribution to the upper and lower layers. The specific modulus demonstrated maximum and average deviations of 10.5% and 4.2%, respectively, while the yield stress exhibited corresponding maximum and average deviations of 14.0% and 6.6%, respectively. The results provide useful references for the design and optimization of hybrid lattice cores. In particular, the findings highlight that the mechanical performance under large-deformation conditions can be enhanced through selective reinforcement strategies, where stronger units are judiciously introduced into critical regions of the core to replace weaker ones. Such a substitution scheme avoids detrimental weakening effects while promoting improved load-bearing capacity and damage tolerance. These insights offer guidance for engineering hybrid sandwich designs capable of meeting specialized demands in extreme service environments.