Titanium alloys are employed in a wide range of applications, from aerospace to medicine. In particular, Ti-6Al-4 V is the most common, thanks to an excellent combination of low density, high specific strength, and corrosion resistance. Laser welding has been increasingly considered as an alternative to traditional techniques to join titanium alloys. An increase in penetration depth and a reduction of possible welding defects are indeed achieved; moreover, a smaller grain size in the fused zone (FZ) is benefited in comparison to either tungsten inert gas (TIG) or plasma arc welding, thus improving the tensile strength of the welded structures. This study was carried out on 3 mm thick Ti-6Al-4 V plates in square butt welding configuration. The novelty element of the investigation is the use of a disk-laser source, which allows a number of benefits thanks to better beam quality; furthermore, a proper device was developed for bead protection, as titanium is prone to oxidation when in fused state. A three-level factorial plan was arranged in face-centered cubic scheme. The regression models were found for a number of crucial responses and the corresponding surfaces were discussed; then a numerical optimization was carried out. The suggested condition was evaluated to compare the actual responses to the predicted values; X-ray inspections, Vickers micro hardness tests, and tensile tests were performed for the optimum.