In this study, the strain hardening behavior and strengthening mechanisms of a mechanically-stable Ti1.6ZrNbAl0.15 lightweight refractory high-entropy alloy (LRHEA) were investigated. The samples were processed by cold-rolling and subsequent annealing to produce fully recrystallized microstructures consisting of a single-phase body-centered cubic (BCC) structure with different mean grain sizes ranging from ∼25 μm to ∼244 μm. The mechanical tests on these samples revealed that grain size refinement had minimal impact on yield strength but effectively improved ductility. Specifically, a low Hall-Petch coefficient of 45 MPa μm1/2, denoting weak grain boundary strengthening, and a high lattice friction stress of 751 MPa, indicating strong solid solution strengthening, were acquired. These findings underscore the significant role played by lattice distortion in contributing to the strength of this LRHEA. Additionally, in the present LRHEA, dislocation structures demonstrated a planar slip dislocation glide mode. No deformation-induced twinning and phase transformation were observed. As the strain increases, the dynamic slip band spacing refinement serves as the primary mechanism for strain hardening, leading to excellent tensile ductility.