Due to low digestibility and long retention time of anaerobic sludge digestion, pre-treatment with alkaline/acid has been widely employed to enhance the rate and extent of sludge digestion. Nonetheless, effects of gradient concentrations of alkaline/acid pre-treatments and resulting salinity on digestion performance and sludge microbiome remain poorly understood. To elucidate these effects, both batch- and reactor-experiments were setup with varied feeding sludge. Significant digestion improvement and sludge microbiome changes were observed with alkaline/acid sludge pre-treatment, compared to non-pretreatment controls, e.g., (similar to)88% increase of carbon removal in sludge digesters. Surprisingly, with the same concentration of influent sludge, no notable change in digestion performance and sludge microbiome was observed in digesters when increasing alkaline/acid concentrations from 0.25 to 0.8 mol/L, and in batch serum bottles with or without NaCl amendment. Consequently, organic compounds dissolved in sludge pre-treatment could be a predominant selective pressure driving the performance and microbiome changes. By contrast, salinity as a consequence of the alkaline/acid pre-treatment could only enrich specific lineages, without altering the overall community profile and function. Together, this study provided insights into specific impacts of major factors on digester performance and sludge microbiome, and shed lights on optimization of sludge digestion.