The lack of fundamental understanding of the chemistry governing elemental mercury (Hg0) immobilization over metal chalcogenides (MChals) is the key challenge impeding the interpretations of Hg0 behaviors in global cycles. This work therefore made the first endeavor toward the establishment of a roadmap capable of describing and depicting Hg0 sequestrations by various MChals. The results suggest that the binding energy between the metal cations and chalcogen anions is a proper descriptor that could predict the immobilization behaviors of Hg0 over zinc chalcogenides (ZnS and ZnSe) that exhibit an identical molecular structure, i.e., the lower the binding energy was, the higher the Hg0 sequestration performance that was obtained. The validity of this descriptor was further demonstrated over a series of MChals sharing structural similarities. A scaling relationship was thus established, which further proved the Hg0 immobilization performance of MChals was generally in reverse proportion to the above-mentioned binding energy. Although there is still a long way toward the proposal of a full roadmap that can predict and depict the Hg0 immobilization behaviors over all MChals, this work marks the first step on this road and provides guides for further studies by understanding the fundamentals governing Hg0 sequestration over MChals with structural similarities.