The use of electrolytic-manganese residue (EMR) as partial cement replacement is a high value-added utilization way, but high-content gypsum in EMR restricts this utilization. This study reports a new desulphurized EMR (D-EMR), which aims to remove this barrier. The engineering performances, environmental safety, and economic efficiency were thoroughly evaluated. Particularly, novel thermodynamic modelling, combined with progressive leaching, was developed to reveal the leaching behaviors of heavy metals. The results show that D-EMR presents a low hydraulicity and slight pozzolanic activity. At a 10% replacement level, the composite sample obtains comparable microstructure and macro-properties to the plain cement sample and causes no leaching and radiological hazards. At higher replacement levels, the composite pastes do not pose leaching risks either, provided their inner pH is above 7.5 due to the buffering capacity of hydrates (pH: above 8) and D-EMR (pH: 7.5–8). In addition, from the environmental perspective, desulphurization is economically acceptable.