Background: Porous polymer scaffolds are commonly used for regenerative medicine and tissue-engineered therapies in the repair and regeneration of structural tissues which require sufficient mechanical integrity to resist loading prior to tissue ingrowth. Objective: Investigate the connection between scaffold architecture and mechanical response of collagen scaffolds used in human tissue-engineered cartilage. Methods: We performed multi-scale mechanical analysis on two types of porous collagen scaffolds with honeycomb and sponge architectures. Confined compression testing was used to assess global non-linear mechanical response of scaffolds. Additionally, we performed confocal strain mapping combined with digital image correlation (DIC) to visualize local mechanical instabilities and compared local strain distributions between scaffold architectures. Results: The global response of both scaffold architectures followed a pattern characteristic of cellular solids, with a linear region, a plateau region, and a densification region. Macro-scale non-linear responses corresponded to local-scale instabilities such as snap-through buckling. On the local-scale, a construct’s compressive response depended heavily on the architecture type. Scaffolds with honeycomb architecture experienced a unimodal strain distribution throughout the scaffold depth. In contrast, scaffolds with sponge architecture tended to collapse at the boundaries. Conclusions: We demonstrated that differences in mechanical response between scaffold architectures were detected primarily at the micro-scale which stems from the disparity in pore architecture. As such, tools like confocal strain mapping combined with DIC are critical for designing and optimizing architectures for porous materials. Observing local instabilities in porous materials is important not only for tuning mechanical response, but also for controlling mechanical events that influence cellular and tissue behavior. © 2022, Society for Experimental Mechanics.