Although coastal organisms experience natural and anthropogenic stressors simultaneously across multiple spatial and temporal scales, the synergistic effects of multiple stressors are largely unknown. In urbanized estuaries, coastal acidification (CA) can be caused by eutrophication (i.e. nutrient loading). CA is strongly associated with a second anthropogenic stressor, sewage effluent (SE). SE can cause acidification locally by increasing nitrogen (N) loads and stimulating algal and microbial production of CO2. Even treated SE can cause CA because excess N is often removed with microbial treatments, leading to effluent that is low in N but has decreased pH and increased concentrations of CO2. The physiological effects of CA and SE have been well characterized separately but have never been examined together in early life history stages when organisms are most sensitive to stressors. Additionally, results from many studies have not been examined in a mechanistic framework, such as identifying the genes that provide resistance to multiple stressors. Here, we use multiple factorial exposures on eastern oyster larvae to characterize the effects of CA and SE on larval mortality and use expressed exome capture sequencing to detect which genetic variants lead to resistance and potential adaptation. Results indicate that CA, SE, and CASE induce clear changes in the allelic composition of larval pools and that the CASE treatment did not represent a composite of the CA and SE treatment. Higher gene ontologies for outlier loci appear to be related to chemical and stress response, supporting the possibility of adaptive resistance to multiple stressors.