Bioanalytical tools are increasingly being employed for water quality monitoring, with applications including samples that are rich in natural organic matter (or dissolved organic carbon, DOC), such as wastewater. While issues associated with co-extracted DOC have been identified for chemical analysis and for bioassays with isolated enzymes, little is known about its effect on cell-based bioassays. Using mixture experiments as diagnostic tools, this study aims to assess whether different molecular weight fractions of wastewater-derived DOC adversely affect cell-based bioassays, specifically the bioluminescence inhibition test with the bacteria Vibrio fischeri, the combined algae assay with Pseudokirchneriella subcapitata and the human cell line AREc32 assay for oxidative stress. DOC did not cause suppressive effects in mixtures with reference compounds. Binary mixtures further indicated that co-extracted DOC did not disturb cell-based bioassays, while slight deviations from toxicity predictions for low molecular weight fractions may be partially due to the availability of natural components to V. fischeri, in addition to organic micropollutants.