Challenges in dissimilar materials welding are the differences of physical and chemical properties between welding materials and the formation of intermetallic brittle phases resulting in the degradation of mechanical properties of welds. However, dissimilar materials welding is increasingly demanded from the industry as it can effectively reduce material costs and improve the design. In aerospace applications, Ti-6Al-4V titanium alloy and Inconel 718 nickel alloy have been widely used because of their superior corrosion resistance and mechanical properties. In this study, a single-mode continuous-wave fibre laser was used in butt welding of Ti-6Al-4V to Inconel 718. Investigations including metallurgical and mechanical examinations were carried out by means of varying processing parameters, such as laser power, welding speed and the laser beam offset position from the interface of the metals. Simple analytical modelling analysis was undertaken to explain the phenomena that occurred in this process. Results showed that the formation of intermetallic brittle phases and welding defects could be effectively restricted at welding conditions produced by the combination of higher laser power, higher welding speed and shifting the laser beam from the interface to the Inconel 718 alloy side. The amount of heat input and position of laser beam to improve the Ti-6Al-4V/Inconel 718 weld quality are suggested.