This paper investigated the effect of post-weld heat treatment (PWHT) on microstructure evolution and sulfide stress corrosion cracking (SSCC) behavior of the fusion boundary (FB) region of Inconel 625/X80 weld overlay, with a focus on the partially mixed zone (PMZ). Three heat treatment regimens were designed, namely 620 °C/10 h, 620 °C/20 h, and 670 °C/10 h, in which 620 °C/20 h was proved to be the optimal parameter. The 10-hour PWHT conditions might induce heterogeneous carbon distribution owing to insufficient tempering duration, exacerbating the hardness mismatch in the FB region and thus promoting the development of SSCC. Following the 620 °C/20 h treatment, most of the brittle phase with high hardness in the FB region was eliminated, reducing the nucleation site for SSCC. More importantly, martensite in the PMZ was transformed into austenite with rod morphology, while cementite adjacent to the PMZ might evolve into dispersed refined austenite. Austenite shows low hydrogen sensitivity, enhancing the SSCC resistance of the PMZ. On the other hand, the carbides in the X80 matrix might restrict the diffusion of hydrogen toward the PMZ, thereby reducing the susceptibility of the PMZ to SSCC.