Nanoindentation test, transmission electron microscopy (TEM) and scanning electron microscopy (SEM) were introduced to investigate the mechanical properties and microstructure of microscopic regions of the nickel-based welded joint. Five indentation series were performed across the weld zone including base metal (BM), coarse grained heat affected zone (CGHAZ), partially melted zone (PMZ), weld metal near the partially melted zone and weld metal center (WM). The mechanical properties (E, H, and n) were then estimated from the load on sample-displacement into surface curves (P-h) data of nanoindentation and SEM analysis results. The results showed that the average nano-hardness value (H) was obviously increased in the CGHAZ. WM has the highest values of elastic modulus (E). BM has the highest plastic rheology stress exponent (n). At the same time, the relationship between the plastic rheology depth and the plastic rheology was also discussed.