In this study, an investigation was carried out to establish a correlation between microhardness and microstructure in dissimilar combination of QP980 and SPFC780Y high strength steel resistance spot welds. Optical microscope with a scanning electron microscope were used for metallography analysis for all regions of the weldment, while Vickers microhardness was implemented to present the hardness profile. It was observed that high heat input provided by high welding current and welding time can increase the mechanical performance and present the hard martensite in the fusion zone (FZ). Softening phenomena were observed in the heat-affected zone (SCHAZ) of both materials with a higher occurrence in SPFC780Y side attributed to the presence of tempered martensite. The microhardness of the FZ was found to be lower than the UCHAZ of QP980 as a result of SPFC780Y dilution in FZ affecting its chemistry and thus hardenability, microstructure and mechanical performance. The study confirms that a significant content of Silicon (Si) and Manganese (Mn) positively contributes to improving mechanical performance. Furthermore, the study introduces an effective method to confirm the symmetry of the weld and FZ chemical composition induced by the asymmetric thermophysical properties in the studied combination. It also allows for the prediction of the occurrence of softening phenomena before the welding operation, providing valuable insights for optimizing the resistance spot welding processes.