Introductions of dreissenid mussels in North America have been a significant concern over the last few decades. This study assessed the distribution of synthetic organic compounds (SOCs) in the food web of Lake Mead, Nevada/Arizona, USA and how this distribution was influenced by the introduction of invasive quagga mussels. A clear spatial gradient of SOC concentrations in water was observed between lake basins downstream of populated areas and more rural areas. Within the food web, trophic magnification factors (TMF) indicated statistically significant biomagnification for nine, and biodilution for two, of 22 SOCs examined. The highest value recorded was for PCB 118 (TMF, 5.14), and biomagnification of methyl triclosan (TMF, 3.85) was also apparent. Biodilution was observed for Tonalide® (0.06) and Galaxolide® (0.38). Total SOC concentration in quagga mussels was higher than in three pelagic fishes. Also, 19 of 20 SOC examined in Largemouth Bass (Micropterus salmoides) had substantially lower concentrations in 2013, when quagga mussels had become well established, than in 2007/08, soon after quagga mussels were introduced. Estimates of SOC concentrations in the water column and quagga mussels suggest that a considerable portion (~10.5%) of the SOC mass in the lake has shifted from the pelagic to the benthic environments due to quagga mussel growth. These observations suggest that benthic species, such as the endangered Razorback Sucker, may be experiencing increased risk of SOC exposure. In addition, stable isotope analysis (carbon and nitrogen) indicated a decrease in the nutritional value of zooplankton to consumers (e.g., Razorback Sucker larvae) since quagga mussels became established. These changes could affect Razorback Sucker larval survival and recruitment. Results from this study strongly suggest that the introduction of quagga mussels has greatly altered the dynamics of SOCs and other processes in the food web of Lake Mead.