His main scientific focus lies in the fields of Theoretical Solid State Physics, Surface Sciences and Computational Materials Physics. His work on ab initio density functional theory for solids, liquid and amorphous systems and surfaces has contributed significantly to basic and applied research and has shaped the application of density functional theory worldwide. Kresse is the main author of the computer code "VASP" (Vienna ab initio simulation package) which his research group develops. VASP is the internationally most widely used program for quantum mechanical simulations of condensed matter. The publications on which this code is based received between 50.000 and 90.000 citations each and are amongst the 100 most cited research articles worldwide ever published.

Until 2019, Kresse directed the Special Research Area "Vienna Computational Materials Laboratory" funded by the Austrian Science Fund. The main goal of this large collaborative project was the precise description of electron interactions in solids and real materials. Currently he is deputy speaker of the SFB TACO (Taming complexity, a catalysis related project).

His current research focus is on machine learning and the accurate prediction of mechanical, electronic and optical properties in condensed matter beyond simple mean field methods, a research area to which he has already made significant contributions. Georg Kresse is the author of about 350 research articles and has an h-index of over 130.