Laser and electron beam (EB) based directed energy deposition (DED) additive manufacturing (AM) processes, followed by hot isostatic pressing (HIP), are potential routes for producing large Ti-6Al-4V structures. Changes in the heat input between the laser DED and EB DED processes impacted the as-deposited and HIP post processed microstructures and mechanical properties for different wall thicknesses and orientations. The significantly lower as-deposited strengths observed in the higher heat input EB DED builds were attributed to losses of important alloying elements and coarsening of prior beta (beta) grains and alpha (alpha) lath structures. These coarsened microstructural features also produced similar properties across the builds, minimizing location and orientation specific changes in properties observed in the laser DED builds. When materials were subjected to HIP post processing, the alpha-lath structures further coarsened in both the laser DED and EB DED builds, leading to a general decrease in strength. A comparison between the as-deposited and HIP yield strengths showed that the higher strength as-deposited laser DED builds displayed larger decreases in strength than the EB DED builds after HIP post processing. However, the orientation specific strength relationships observed in the as-deposited laser DED builds were only reduced and not eliminated after HIP post-processing. Interactions between chemical composition and alpha-lath thickness on the mechanical properties were further evaluated using a conventional strengthening model, and the magnitude of each contribution on yield strength was determined for each processing route in the as-deposited and HIP conditions.