The influence of keyhole TIG (K-TIG) welding parameters on the weld geometry and defects of a new nickel-based superalloy VDM Alloy 780 alloy were investigated using a statistical design of experiment, and the microstructures of the heat-affected zone (HAZ) and fusion zone (FZ) of the K-TIG-welded VDM Alloy 780 were characterized. No cracks are found in the FZ and HAZ. Travel speed significantly influences the minimum weld width (Wm), face and root excess weld metal, face underfill, and average pore diameter. Welding current and the interaction current*travel speed significantly influence the face and root excess weld metals, respectively. Interdendritic microconstituents in the FZ are identified as (Nb,Ti)C particles and γ/Laves eutectic constituents based on SEM–EDS analysis. In addition, plate-like precipitates likely to be δ/η phase are observed surrounding the interdendritic Laves eutectics, and γ′ precipitates are found to be inhomogeneously precipitated in the FZ. In the partially melted zone (PMZ), (Nb,Ti)C, Laves phase, and plate-like particles are found in the liquated and resolidified regions. Constitutional liquation of (Nb,Ti)C in HAZ is observed where the liquated (Nb,Ti)C appears to be associated with the γ/Laves eutectic as a resolidified product.