Bioneutralization of pH by microbial fermentation of added carbon substrates is a promising new method for remediation of the 1.7 GT/yr of alkaline mining tailings produced globally. Here, we present the first study to systematically compare and optimize the efficacy of microbial inocula of varying diversities, structures, and provenance and organic carbon substrates of varying complexities on the rate and extent of pH bioneutralization in alkaline bauxite residue tailings. Laboratory-scale bioreactors inoculated with soda lake sediments or with monosaccharide substrates added had a significantly lower minimum pH (<8) and a significantly higher maximum rate of pH neutralization (>0.02 μmol H+ day-1) and achieved these in significantly less time (<26 days) compared to bioreactors with other inocula or substrates. The soda lake sediment introduced a significantly higher-diversity microbial community with a distinct structure (dominated by Euryarchaeota and Bacteroidetes, rather than Acidobacteria and Actinobacteria), supporting higher acetate and formate-yielding fermentation pathways compared to other inocula. The strong performance of monosaccharides is attributed to widespread microbial capacity for efficient fermentation. Using either monosaccharide carbon substrates or soda lake sediments is recommended to maximize bioneutralization efficiency at the industrial scale.