© 2020, Springer-Verlag London Ltd., part of Springer Nature. The present study centres on the effect of post-weld heat treatment (PWHT) on microstructure and mechanical properties of the deep penetration keyhole Tungsten Inert Gas (K-TIG) welded dissimilar joint between creep strength enhanced ferritic (CSEF) steel and austenitic stainless steel (ASS). The as-received normalized and tempered CSEF steel was joined with ASS in a single pass without using any filler materials and edge preparation. Detailed characterization across the welded joint was conducted using stereomicroscope, electron microscopy, energy dispersive spectroscopy (EDS), electron backscattered diffraction (EBSD), hardness test, tensile test and Charpy impact test. Results showed that PWHT had significant effect on the microstructure and mechanical properties of both the weld metal and CSEF steel heat-affected zone (HAZ), while it had little influence on the ASS side. By using proper PWHT, the hardness gradient across the welded joint could be mitigated and toughness in both the weld metal and the CSEF steel HAZ could be restored. 760 °C was considered the most appropriate PWHT temperature for such dissimilar joint in terms of the overall mechanical properties. The tensile properties of K-TIG welded joint after PWHT were comparable to both friction stir welded joint and laser and/or electron beam welded joint, indicating that deep penetration TIG welding technology may provide a good alternative for the nuclear industry. The correlation among welding thermal cycle, various heat treatment, microstructure evolution and mechanical properties was also analysed in detail.