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Following the Deepwater Horizon oil spill, eastern oyster (Crassostrea virginica) reefs in the northern Gulf of Mexico were exposed to oil and various associated clean-up activities that may have compromised oyster reef health. Included in the exposure was oil, dispersant, and in some locales, atypical salinity regimes. Oil and dispersants can be detrimental to oysters and the effects of salinity depend on the level. In addition to these extrinsic factors, genetic diversity of oyster populations may help the oysters respond to stressors, as demonstrated in other systems. We used a 3×3×2 factorial design to experimentally examine the effects of oil/dispersed oil, intraspecific genetic diversity, and salinity on juvenile (ca. 25 mm shell height) oyster survivorship and growth during a 21-d exposure in a closed, recirculating system. The genetic effect was weak overall, oil and dispersed oil negatively affected juvenile oyster survivorship, and low salinity mitigated mortality in oil and dispersed oil treatments. Survivorship was about 40% greater in low-salinity than in mesohaline water for both oil and dispersed oil treatments, bringing survivorship in low salinity oil-only treatments to a similar level with low salinity controls (no oil). Oyster growth was minimal after 21 d but appeared to be negatively affected by oil and dispersed oil, and had a significant interaction with salinity. Our results may be informative for future decisions regarding oil spill response activities and suggest that a pulse of low salinity water may be a viable short-term mitigation option for oysters if filtration characteristics, exposure time, and water temperatures are all considered, in addition to weighing the costs and benefits of this type of response on other organisms and habitats.