Concerns regarding disinfection by-product (DBP) formation during drinking water treatment have led water utilities to apply treatment processes to reduce the concentration of DBP precursor natural organic matter (NOM). However, these processes often do not remove bromide, leading to high bromide to dissolved organic carbon (DOC) ratios after treatment, which can increase the formation of more toxic brominated DBPs. In the current study, we investigated the formation and effect of DBPs in a matrix of synthetic water samples containing different concentrations of bromide and DOC after disinfection with chlorine. Trihalomethanes and haloacetic acids were analysed by chemical analysis, while effect was evaluated using in vitro bioassays indicative of the oxidative stress response and bacterial toxicity. While the addition of increasing bromide concentrations did not alter the sum molar concentration of DBPs formed, the speciation changed, with greater bromine incorporation with an increasing Br:DOC ratio. However, the observed effect did not correlate with the Br:DOC ratio, but instead, effect increased with increasing DOC concentration. Water samples with low DOC and high bromide did not exceed the available oxidative stress response effect-based trigger value (EBT), while all samples with high DOC, irrespective of the bromide concentration, exceeded the EBT. This suggests that treatment processes that remove NOM can improve drinking water quality, even if they are unable to remove bromide. Further, iceberg modelling showed that detected DBPs only explained a small fraction of the oxidative stress response, supporting the application of both chemical analysis and bioanalysis for monitoring DBP formation.