Cadmium, an extremely toxic heavy metal, poses significant health risks to humans. Despite persistent research efforts, the development of effective treatments for cadmium intoxication remains a challenge. This study aims to establish the chemical groundwork for improved chelation therapy options against cadmium poisoning. Herein, the coordination chemistry of a series of sulfur-rich macrocycles featuring different polyamine backbones (NO3S, TACD3S, DO4S, TRI4S, and TE4S) was investigated. Our results demonstrate that DO4S exhibits exceptional Cd2+ scavenging ability, forming the most thermodynamically stable complex among the studied chelators. The stability of the Cd2+ complexes decreases in the following order: DO4S (pCd = 19.8) ≫ NO3S (pCd = 11.0) ∼ TRI4S (pCd = 10.9) ≫ TE4S (pCd = 7.8) > TACD3S (pCd = 7.3). DFT calculations demonstrated that the backbone polarization properties dictate the observed reduced stability when shifting from DO4S to the other ligands. DO4S showed superior affinity when compared to the state-of-the-art Cd2+ chelators such as EDTA (pCd = 16.7), DTPA (pCd = 17.4), and DMSA (pCd = 13.2). The findings from this study underscore the potential of the examined chelating agents, with particular reference to DO4S, paving the way for the development of advanced chelation therapies to combat cadmium poisoning.