Bisulfite-activated permanganate oxidation (PM/BS) technology is an emerging oxidation process that can rapidly oxidize organic contaminants and degrade some permanganate-resistant organic contaminants. For the first time, the influences of PM/BS technology as a pre-oxidation process on the formation potentials of disinfection by-products (DBPFPs) during chlorination of humic acid (HA) solution and three natural water samples were investigated. The results revealed that PM/BS pre-oxidation only slightly affected the DBPFPs of HA in the absence of Br- although it changed the structure of HA according to the fluorescence characterization result. With the presence of Br-, PM/BS pre-oxidation enhanced the generation of trihalomethanes but inhibited that of nitrogenous DBPs (N-DBPs) during chlorination of HA. The toxic risk analysis showed that the toxicity of the generated DBPs from chlorinating HA solution without Br- only changed slightly after PM/BS pre-oxidation but it was decreased by 14% in the presence of 150 μg/L Br− due to PM/BS pre-oxidation. This should be associated with the inhibiting effect of PM/BS pre-oxidation on the generation of N-DBPs and several haloacetic acids in the presence of Br-. Because of the complex matrix of natural water samples, PM/BS pre-oxidation had minor influence on the amount and the potential toxicity of DBPs generated during chlorination. The above results suggested that PM/BS technology could be an alternative of the drinking water pretreatment.