Under mechanical loading, the strain hardening behavior of crystalline face-centered cubic (FCC) metals is of critical importance in determining fracture behavior and overall mechanical performance. While strain hardening is typically accompanied by a decrease in ductility, it can also simultaneously enhance the material's resistance to plastic deformation and improve its load bearing capacity. Hence, we conducted a detailed study using copper (Cu) single-crystal micropillars as a model system to investigate and delineate the relationship between strain hardening and defect behavior. We employed in situ compression in a scanning electron microscope (SEM) and dislocation density-based crystal plasticity (DCP) modeling. The strain hardening rate varied with the compression crystallographic orientation, ranging from negligible values (of approximately 80 MPa) to relatively high hardening rates (of approximately 1150 MPa) for nominal strains of up to 15%. Various analysis methods were applied, including slip trace characterization, electron backscatter diffraction (EBSD), transmission electron microscopy (TEM), and transmission Kikuchi diffraction (TKD). These techniques allowed us to identify the distributions of active slip systems, dislocation structures after compression, and correlated internal lattice rotations. Furthermore, the DCP model was developed to specifically understand how serration events are related to dislocation-density evolution or strain bursts, and this was validated with the micropillar experiments. This integrated experimental and modeling investigation offers valuable insights and predictions regarding the evolution of both total and partial dislocations, including Hirth and Lomer junctions, as well as lattice rotations.