In this study, 2195 Al–Cu–Li alloys with a remarkable layered structure were fabricated through spray deposition, hot extrusion, and three distinct heat treatment processes (namely, solid solution treatment (ST), artificial peak-aging (PA), and artificial over-aging (OA)). The samples subjected to varying heat treatments are revealed to exhibit an exceptional combination of strength and ductility at 77 K, in contrast to their counterparts at 298 K. Specially, the mechanical properties of the PA samples are enhanced to various degrees with decreasing temperature from 298 K to 77 K. It is found that the synergistic effects of dense dislocations and uniform T1 precipitates, as well as their extensive interactions, are responsible for the exceptional strain hardening capacity at cryogenic temperature. Particularly, multiple slip systems and the temperature-dependent relative slip distance are beneficial for the formation of dense dislocations and thus for enhancing ductility at 77 K. Furthermore, the observation of rare and small microcracks, along with intergranular delamination at 77 K, suggests that layered structures impede the plastic instability of the alloy and improve its ductility. These findings provide valuable insights into the deformation behaviors of high-strength aluminum alloys for cryogenic applications.