Dissimilatory sulfate reduction–based processes have long been a viable option for treating acidic metal-laden wastewater (AMW). Such processes can be optimized through enhancing sulfidogenic activity and the microbial consortia's resilience against a harsh environment. This study investigated how granular and flocculent sulfate-reducing bacteria (SRB) sludge respond to AMW as well as the mechanisms through which they adapt to the wastewater, with particular focuses on the stability of the sulfidogenic activities, metal removal, and the bacteria's resistance over the long-term: the flocculent SRB lost more than 50% of their treatment capacity after 35 days of treating AMW with the presence of Cd, Cu, Zn, and Ni at 30 mg/L each, under pH = 4.5. In contrast, the granular SRB maintained its metal removal rate at 91% throughout the 161-day trial. Despite the SRB abundance remaining at approximate 40%, organics-partial oxidizing genera (Desulfobulbus and Desulfobacter) began to dominate due to their kinetic advantage. The extracellular glycosyl compositions were revealed to be critical for the stability of the granular structure and microbial activity as the extracellular proteins disintegrated irreversible. Usage the molecular dynamic simulation, the mobility of the metal ions in the SRB granular system was suppressed by the presence of a more diverse glycosyl composition compared with the flocculent system (10–50% diffusion coefficients differences). All of the identified glycosyls (especially xylose and rhamnose) exhibited strong interactions with Cu (-470 kJ mol), while the maximum binding strength of Cd to glycosyls was greater than -40 kJ mol, suggesting a low Cdcomplexation efficiency. The findings of this study shed light on the defensive mechanisms of SRB granules against multi-metal stress, and provide clues for efficient AMW treatment.