Triploid oysters are commonly used as the basis for production in the aquaculture of eastern oysters along the U.S East and Gulf of Mexico coasts. While they are valued for their rapid growth, incidents of triploid mortality during summer months have been well documented in eastern oysters, especially at low salinity sites. Various factors, including parental contribution, gametogenesis failures, as well as cellular and physiological issues stemming from their polyploid state have been proposed as potential causes of triploid mortality, but the exact molecular and physiological mechanisms remain unresolved. We used comparative transcriptomics to examine global transcriptomic responses at the onset of summer mortality (July 2020) in diploid and triploid oysters outplanted to a high and low salinity site, to detect unique gene expression patterns associated with outplant site, maternal broodstock, and ploidy. Diploid dams from three different salinity regimes were used to generate diploid and triploid oyster lines that were spawned at two hatcheries and were outplanted to high (annual mean salinity = 19.4 ± 6.7) and low (annual mean salinity = 9.3 ± 5.0) salinity sites. Our DEG analyses comparing diploid and triploid oysters detected very few DEGs across the three dams, indicating that diploid parentage was not a key contributing factor to triploid mortality. We detected a higher number of DEGs across outplant sites and cohorts, indicating stronger influence of these two factors on triploid mortality. At the low salinity site where triploid oysters experienced high mortality, we observed downregulation of GO terms related to calcium signaling, ciliary activity, and cell cycle check points. These GO terms implicate mis regulation of the low salinity stress response and problems during cell division as key contributors to elevated summer mortality in triploid oysters.